Pharmaceutical piperazine compounds

ABSTRACT

PCT No. PCT/GB95/00299 Sec. 371 Date Sep. 24, 1996 Sec. 102(e) Date Sep. 24, 1996 PCT Filed Feb. 14, 1995 PCT Pub. No. WO95/21829 PCT Pub. Date Aug. 17, 1995Diketopiperazines of formula (A): wherein each of R1 to R8 is H or an organic radical as described herein and the pharmaceutically acceptable salts thereof have activity as inhibitors of plasminogen activator inhibitor.

The present invention relates to compounds useful as inhibitors ofplasminogen activator inhibitor (PAI), to their preparation and topharmaceutical and veterinary compositions containing them.

Plasminogen activators (PAs) are serine proteases which control theactivation of the zymogen, plasminogen, to the active enzyme plasmin.Plasmin is important in a number of physiological and pathologicalprocesses including fibrinolysis, tissue remodelling, tumour growth andmetastasis. The glycoprotein plasminogen activator inhibitor (PAI) is anendogenous fast-acting inhibitor of PA activity. PAI is a member of theserpin family and is synthesized by a variety of cells includingendothelial cells. An imbalance between PAs and PAI contributes to anumber of pathological conditions including haemostasis, inflammation,tumour growth and metastasis.

The present invention provides a diketopiperazine of formula (A):##STR2## wherein R₁ is H, a halogen, --COOR₁₁, C₁ -C₆ alkyl, NO₂, C₁ -C₆alkoxy, --NHCOCH₃ or CF₃ ;

R₂ is H, --O(CH₂)_(n) N(R₁₁ R₁₂), C₁ -C₆ alkyl, NO₂, CN, halogen, C₁ -C₆alkoxy, CF₃, OCF₃, --NHCOCH₃ or phthalimido;

R₃ is H, --O(CH₂)_(n) N(R₁₁ R₁₂), halogen, C₁ -C₆ alkoxy, NO₂, C₁ -C₆alkyl, CF₃, CN, --CON(R₁₁ R₁₂), --NHCOCH₃, --CO₂ R₁₁, --CONH(CH₂)_(n)Ph, SR₁₃ or --(CH₂)_(n) N(R₁₁ R₁₂); or R₂ and R₃ together form amethylenedioxy group --OCH₂ O--;

R₄ is H, halogen, NO₂ or --O(CH₂)_(n) N(R₁₁ R₁₂);

R₅ is H or a halogen;

R₆ is H, a halogen or --O(CH₂)_(n) N(R₁₁ R₁₂);

R₇ is H, --O(CH₂)_(n) N(R₁₁ R₁₂) or C₁ -C₆ alkoxy; and

R₈ is H, a halogen, --O(CH₂)_(n) N(R₁₁ R₁₂), --CH₂ Y(CH₂)_(n) N(R₁₁R₁₂), --OC(O) (CH₂)_(n) R₁₁, C₁ -C₆ alkoxy, --(CH₂)_(n) NHCO(CH₂)_(n)CO₂ R₁₁, --(CH₂)_(n) N(R₁₁ R₁₂) --CH₂ N (CH₂)_(n) N(R₁₁ R₁₂)!₂, or--O(CH₂)_(n) CO₂ H

wherein n is 0 or an integer of 1 to 6, Y is O or S, each of R₁₁ and R₁₂is, independently, hydrogen or a straight or branched C₁ -C₆ alkyl andR₁₃ is straight or branched C₁ -C₆ alkyl; or a pharmaceuticallyacceptable salt or ester thereof;

with the exception of compounds wherein

(i) each of R₁ to R₈ is H;

(ii) R₁ and R₆ are both Cl or Br and the rest of R₁ to R₈ are H;

R₃ and R₈ are the same and are both F, Cl or OMe and the rest of R₁ toR₈ are H; and

(iii) R₈ is OMe and the rest of R₁ to R₁₀ are H.

The numerals 1 to 10 denote ring positions on the phenyl groups informula A. The letters a and b refer to the two phenyl rings themselves.

A C₁ -C₆ alkyl group is typically a C₁ -C₄ alkyl group, for example amethyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group.A halogen is, for example, fluorine, chlorine, bromine or iodine.

A C₁ -C₆ alkoxy group is typically a C₁ -C₄ alkoxy group, for example amethoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxygroup.

A group --CH₂ Y(CH₂)_(n) N(R₁₁ R₁₂) is preferably a group --CH₂O(CH₂)_(n) NMe₂ or --CH₂ S(CH₂)_(n) NMe₂ wherein n is from 1 to 3.

In compounds of formula A free rotation may occur at room temperatureabout the single bonds connecting rings a and b to the double bonds atpositions 3 and 6 of the piperazine-2,5-dione ring. Positions 2 and 6,and positions 3 and 5, in both rings a and b can therefore be consideredas equivalent. As a consequence the following pairs of substituents canbe viewed as interchangeable: R₁ and R₅ ; and R₂ and R₄.

Preferably one of rings a and b is unsubstituted or is mono-substitutedwhilst the other ring is unsubstituted or is substituted at one or moreof positions 2 to 6. The ring which is mono-substituted may carry thesubstituent at any one of positions 2 to 6, for instance position 3 or4, especially position 4. Thus for instance, when ring b ismono-substituted, one of R₆ to R₈ is other than hydrogen, preferably R₇or R₈, especially R₈. When ring a is mono-substituted, one of R₁ to R₅is other than hydrogen, preferably R₂ or R₃, especially R₃. When one ofrings a and b is mono-substituted the substituent R₁ to R₅, or R₆ to R₈respectively, is preferably selected from --O(CH₂)_(n) N(R₁₁ R₁₂),especially --O(CH₂)₂ NMe₂ or --O(CH₂)₃ NMe₂ ; --CH₂ Y(CH₂)_(n) N(R₁₁R₁₂); a halogen, for instance fluorine or chlorine; and an alkoxy group,for instance OMe.

When one of rings a and b is unsubstituted, or is mono-substituted asdescribed in the above paragraph, the other ring may bear any desiredsubstitution pattern. For instance, the other ring may be unsubstitutedor may be mono-, di- or tri-substituted at any of positions 2 to 6 inthe case of ring a, or at any of positions 2 to 4 in the case of ring b.

The said other ring may, for instance, be mono-substituted at any ofpositions 2 to 6, when it is ring a, or positions 2 to 4 when it is ringb. Ring a may also be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-disubstituted,or 2,3,4-, 2,3,5-, 2,3,6- or 3,4,5-trisubstituted. Ring b may be 2,3 or2,4 disubstituted, or 2,3,4-trisubstituted. Thus, when the said otherring is a and is mono-substituted, four of R₁ to R₅ are hydrogen and oneis other than hydrogen. When the said other ring is ring a and isdisubstituted, three of R₁ to R₅ are hydrogen and two are other thanhydrogen. For example R₁ and R₂, or R₁ and R₃, or R₁ and R₄, or R₁ andR₅, or R₂ and R₃, or R₂ and R₄ are other than hydrogen whilst, in eachcase, the other three of R₁ to R₅ are hydrogen.

When the said other ring is ring a and is trisubstituted, two of R₁ toR₅ are hydrogen and three are other than hydrogen. For example, R₁, R₂and R₃, or R₁, R₂ and R₄, or R₁, R₂ and R₅, or R₂, R₃ and R₄ are otherthan hydrogen whilst, in each case, the other two of R₁ to R₅ arehydrogen.

When the said ring is b and is mono-substituted, two of R₆ to R₈ arehydrogen and one is other than hydrogen. When the said other ring is band is di-substituted, one of R₆ to R₈ is hydrogen and two are otherthan hydrogen. For example R₆ and R₇, or R₆ and R₈ are other thanhydrogen. When the said other ring is b and is trisubstituted, all threeof R₆ to R₈ are other than hydrogen.

In a preferred series of compounds of formula A each of R₆ and R₇ ishydrogen and R₈ is --O(CH₂)_(n) N(R₁₁ R₁₂) or --CH₂ Y(CH₂)_(n) N(R₁₁R₁₂) as defined above. In another preferred series of compounds, R₈ is--O(CH₂)_(n) N(R₁₁ R₁₂), one of R₆ and R₇ is --O(CH₂)_(n) N(R₁₁ R₁₂) orhalogen and the other of R₆ and R₇ is H. Preferably --O(CH₂)_(n) N(R₁₁R₁₂) is --O(CH₂)₂ NMe₂ or --O(CH₂)₃ NMe₂.

In the above-mentioned series of preferred compounds R₁ to R₅ are allhydrogen, or one or two of R₁ to R₅ are other than hydrogen whilst theothers are hydrogen. For instance one of R₁, R₂ and R₃ is other thanhydrogen. Alternatively R₁ and R₃, or R₂ and R₃, are other thanhydrogen.

Particularly preferred compounds are those wherein R₈ is --O(CH₂)_(n)NMe₂ or --CH₂ Y(CH₂)_(n) N(R₁₁ R₁₂) wherein n is 2 or 3, R₆ and R₇ andeach of R₁ to R₅ is as specified above.

In one embodiment, R₁ is H, Cl Me, MeO, NO₂ or --COOMe;

R₂ is H, Me, MeO, Cl, Br or --O(CH₂)_(n) NMe₂ ; or R₂ and R₃ togetherform a methylenedioxy group --OCH₂ O--;

R₃ is H, OCH₃, OC₆ H₁₄, O(CH₂)_(n) NMe₂ wherein n is 2 or 3, or CH₂ NMe₂;

R₄ is H or --O(CH₂)₂ NMe₂ ;

R₅ is H or Cl;

R₆ is H, Cl or F or --O(CH₂)₂ NMe₂ ;

R₇ is H, --O(CH₂)_(n) NMe₂ wherein n is 1 or 2, or OMe; and

R₈ is H, F, OMe, --O(CH₂)_(n) NMe, --CH₂ S(CH₂)_(n) NMe₂ or --CH₂O(CH₂)_(n) NMe₂ wherein n is 1, 2 or 3, --CH₂ NHCO(CH₂)₃ CO₂ Me, --CH₂NH₂, --(CH₂)_(n) NMe₂ wherein n is 1, 2, 3 or 4; --OCH₂ CO₂ H, --CH₂ N(CH₂)₃ NMe₂ !, or --OCO(CH₂)_(n) R₁₁ wherein n is from 1 to 5 and R₁₁ isCH₃ or t-butyl.

In a second embodiment R⁸ is --O(CH₂)_(n) NMe₂ wherein n is 2 or 3, eachof R₆ and R₇ is H; R₁ is H or Cl; R₂ is H, R₃ is H, C₁ -C₆ alkoxy suchas OMe, --O(CH₂)_(n) NMe₂ wherein n is 2 or 3, or --CH₂ NMe₂ ; R₄ is Hand R₅ is H or Cl.

In a further embodiment, R₁ is H, Cl or --COOMe; R₂, R₃ and R₄ are eachindependently H or --O(CH₂)_(n) NMe₂ wherein n is 1 or 2;

R₅ is H or Cl;

R₆ is H or F;

R₇ is H, OMe or --O(CH₂)_(n) NMe₂ wherein n is 1 or 2; and

R₈ is H, F, or --O(CH₂)₂ NMe₂.

In another embodiment R₈ and one of R₆ and R₇ is, independently,--O(CH₂)_(n) NMe₂ wherein n is 2 or 3, the other of R₆ and R₇ is H; andeach of R₁ to R₅ is H.

In a further embodiment R₈ is --O(CH₂)_(n) NMe₂ wherein n is 2 or 3, R₆is Cl and R₇ is H, or R₆ is H and R₇ is OMe; and each of R₁ to R₅ is H.

In a yet further embodiment each of R₁ to R₅ is H;

R₆ is H, --O(CH₂)_(n) NMe₂, Cl or F;

R₇ is H, --O(CH₂)_(n) NMe₂ wherein n is 1 or 2, or OMe; and

R₈ is H, --OCOCH₂ -^(t) Bu, --O(CH₂)_(n) NMe₂ wherein n is 1 or 2,--NCH₂ NH₂, --CH₂ N (CH₂)₃ NMe₂ ! or --OCH₂ CO₂ H.

Certain diketopiperazines have been disclosed as having utility asbioactive agents. Yokoi et al in J. Antibiotics vol XLI No. 4, pp494-501 (1988) describe structure-cytotoxicity relationship studies on aseries of diketopiperazines related to neihumicin, a compound obtainedfrom the micro-organism Micromonospora neihuensis. Kamei et al in J.Antibiotics vol XLIII No. 8, 1018-1020 disclose that twodiketopiperazines, designated piperafizines A and B, have utility aspotentiators of the cytotoxicity of vincristine.

Examples of specific compounds of formula A are as follows. The compoundnumbering is adhered to in the rest of the specification:

1962(3Z,6Z)-3,6-Di-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedionedihydrochloride.

1953(3Z,6Z)-3-Benzylidene-6-(4-bis(2-dimethylaminopropyl)aminomethylbenzylidene-2,5-piperazinedione.

1961(3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1957(3Z,6Z)-3,6-Di-(4-(2-dimethylaminopropoxy)benzylidene)-2,5-piperazinedionebis methane sulfonate (1:2).

1949(3Z,6Z)-3-Benzylidene-6-(3,4-di-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1952(3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene-2,5-piperazinedione.

1955(3Z,6Z)-3,6-Di-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedionebis hydrogen succinate (1:2).

1913(3Z,6Z)-3-Benzylidene-6-(4-dimethylaminomethylbenzylidene)-2,5-piperazinedione.

1909 Methyl4-(4-((3Z,6Z)-6-(4-Methoxybenzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzylcarbonyl)butanoate.

1885(3Z,6Z)-3-(4-(3,3-dimethylbutanoyloxy)benzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.

1665(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(2-fluorobenzylidene)-2,5-piperazinedione.

1951(3Z,6Z)-3-Benzylidene-6-(2-chloro-4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1969(3Z,6Z)-3-Benzylidene-6-(2,4-di-(2-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

1984(3Z,6Z)-3-Benzylidene-6-(2,4-di-(2-dimethylaminoethoxy)benzylidene-2,5-piperazinedione.

1981(3Z,6Z)-3-Benzylidene-6-(4-bis(3-dimethylaminopropyl)aminomethylbenzylidene)-2,5-piperazinedione.

1908(3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1977(3Z,6Z)-3-(2,4-Difluorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1911(3Z,6Z)-3-(4-(2-Dimethylaminoethoxy)benzylidene)-6-(4-methoxybenzylidene-2,5-piperazinedione.

1946(3Z,6Z)-3-Benzylidene-6-(2-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1924(3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1925(3Z,6Z)-3-(4-Aminomethylbenzylidene)-6-benzylidene-2,5-piperazinedionetrifluoroacetate.

1914(3Z,6Z)-3-Benzylidene-6-(4-dimethylaminobenzylidene)-2,5-piperazinedionehydrochloride.

1907(3Z,6Z)-3-(4-Hexyloxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.

5233(3Z,6Z)-3-(4-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5236(3Z,6Z)-3-(3,4-Dichlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5237(3Z,6Z)-3-(3-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5245(3Z,6Z)-3-(4-Cyanobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5250(3Z,6Z)-3-(4-Butoxybenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5260(3Z,6Z)-3-(4-Aminobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5348(3Z,6Z)-3-(4-Cyanobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5360(3Z,6Z)-3-(4-Bromobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5366(3Z,6Z)-3-(4-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5234(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.

5235(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-methylbenzylidene)-2,5-piperazinedione.

5238(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-tert-butylbenzylidene)-2,5-piperazinedione.

5239(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-trifluoromethylbenzylidene)-2,5-piperazinedione.

5365(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-fluorobenzylidene)-2,5-piperazinedione.

5385(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-methylthiobenzylidene)-2,5-piperazinedione.

5401 Methyl4((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzoate.

52464-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.

53434-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzanilide.

5344N-Benzyl-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.

5345N-Phenethyl-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.

5346N-(3-Phenylpropyl)-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.

5347N-(4-Phenylbutyl)-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.

5186(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-methylbenzylidene)-2,5-piperazinedione.

5187(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-methylbenzylidene)-2,5-piperazinedione.

5201(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3,4-methylenedioxybenzylidene)-2,5-piperazinedione.

5208(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-nitrobenzylidene)-2,5-piperazinedione.

5209(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-nitrobenzylidene)-2,5-piperazinedione.

5210(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-nitrobenzylidene)-2,5-piperazinedione.

5242(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-methoxybenzylidene)-2,5-piperazinedione.

5241(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-methoxybenzylidene)-2,5-piperazinedione.

5251(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-trifluoromethylbenzylidene)-2,5-piperazinedione.

5252(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-trifluoromethylbenzylidene)-2,5-piperazinedione.

5255(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-phthalimidobenzylidene)-2,5-piperazinedione.

5373(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-fluorobenzylidene)-2,5-piperazinedione.

5374(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-trifluoromethoxybenzylidene)-2,5-piperazinedione.

5378(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3,5-dinitrobenzylidene)-2,5-piperazinedione.

5065(3Z,6Z)-6-Benzylidene-3-(4-(2-diethylaminoethoxy)benzylidene-2,5-piperazinedione.

5070(3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-(2-dimethylaminoethoxymethyl)benzylidene)-2,5-piperazinedione.

5080(3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-(2-Dimethylaminoethylthiomethyl)benzylidene)-2,5-piperazinedione.

1634 Methyl2-((3Z,6Z)-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide.

1852(3Z,6Z)-6-Benzylidene-3-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

1887(3Z,6Z)-3-(4-Heptanoyloxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.

1889(3Z,6Z)-6-Benzylidene-3-(4-(3,3-dimethylbutanoyloxy)benzylidene)-2,5-piperazinedione.

1920(3Z,6Z)-3-(4-Butoxybenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

1947(3Z,6Z)-3,6-Di-(3-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1954(3Z,6Z)-6-Benzylidene-3-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1978(3Z,6Z)-6-Benzylidene-3-(3,4-di-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1979(3Z,6Z)-Benzylidene-3-(2-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

1980(3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.

5060(3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5249(3Z,6Z)-3-(2-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5248(3Z,6Z)-3-(2-Acetamidobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.

5256(3Z,6Z)-3-(3-Acetamidobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5372(3Z,6Z)-3-(3,5-Dichlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5375(3Z,6Z)-3-(3-Bromobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5398(3Z,6Z)-3-(4-Chloro-3-nitrobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5023(3Z,6Z)-3-(4-Dimethylaminomethylbenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5048(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5068(3Z,6Z)-3-(4-Dimethylaminobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

5232(3Z,6Z)-3-(3-Cyanobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.

1960(3Z,6Z)-6-Benzylidene-3-(2-chloro-4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione,hydrochloride.

5228(3Z,6Z)-3-(4-(3-dimethylaminopropoxy)benzylidene)-6-(4-nitrobenzylidene)-2,5-piperazinedione.

5058(3Z,6Z)-6-Benzylidene-3-(4-(2-Dimethylaminoethylthiomethyl)benzylidene)-2,5-piperazinedione.

Compounds of formula A may be prepared by a process which compriseseither (i) condensing a compound of formula (I) ##STR3## wherein R₆ toR₁₀ are as defined above and are optionally protected, with a compoundof formula (II): ##STR4## wherein R₁ to R₅ are defined above and areoptionally protected, in the presence of a base in an organic solvent;or (ii) condensing a compound of formula (I'): ##STR5## wherein R₁ to R₅are as defined above and are optionally protected, with a compound offormula (III): ##STR6## wherein R₆ to R₁₀ are as defined above and areoptionally protected, in the presence of a base in an organic solvent;and, in either case (i) or (ii), if required, removing optionallypresent protecting groups and/or, if desired, converting one compound offormula A into another compound of formula A, and/or, if desired,converting a compound of formula A into a pharmaceutically acceptablesalt or ester thereof, and/or, if desired, converting a salt or esterinto a free compound, and/or, if desired, separating a mixture ofisomers of compounds of formula A into the single isomers.

A compound of formula A produced directly by the condensation reactionbetween (I) and (II) or (I') and (III) may be modified, if desired, byconverting one or more of groups R₁ to R₁₀ into different groups R₁ toR₁₀. These optional conversions may be carried out by methods known inthemselves. For example, a compound of formula A in which R₁ is an estergroup may be converted to a compound of formula A wherein thecorresponding substituent is a free --COOH group, by acid or alkalinehydrolysis at a suitable temperature, for example from ambienttemperature to 100° C.

A compound of formula A in which R₁ is a --CO₂ H group may be convertedinto a compound of formula A wherein R₁ is esterified by esterification,for example by treating the carboxylic acid with a suitable C₁ -C₆ alkylalcohol in the presence of 1,3-dicyclohexylcarbodiimide in an inertsolvent.

Protecting groups for R₁ to R₈ in any of the compounds of formulae (I),(I'), (II) and (III) are optionally introduced prior to step (i) or step(ii) when any of groups R₁ to R₈ are groups which are sensitive to thecondensation reaction conditions or incompatible with the condensationreaction, for example a --COOH or amino group. The protecting groups arethen removed at the end of the process. Any conventional protectinggroup suitable for the group R₁ to R₈ in question may be employed, andmay be introduced and subsequently removed by well-known standardmethods.

The condensation reaction between compounds (I) and (II) or (I') and(III) is suitably performed in the presence of a base which is potassiumt-butoxide, sodium hydride, potassium carbonate, sodium carbonate,caesium carbonate, sodium acetate, potassium fluoride on alumina, ortriethylamine in a solvent such as dimethylformamide, or in the presenceof potassium t-butoxide in t-butanol or a mixture of t-butanol anddimethylformamide. The reaction is typically performed at a temperaturefrom 0° C. to the reflux temperature of the solvent.

The compounds of formula (I) may be prepared by a process comprisingreacting 1,4-diacetyl-2,5-piperazinedione with a compound of formula(III) as defined above, in the presence of a base in an organic solvent.Similarly, the compounds of formula (I') may be prepared by a processwhich comprises reacting 1,4-diacetyl-2,5-piperazinedione with acompound of formula (II) as defined above, in the presence of a base inan organic solvent.

If necessary, the resulting compound of formula (I) or (I') can beseparated from other reaction products by chromatography.

The reaction of 1,4-diacetyl-2,5-piperazinedione with the compound offormula (III) or (II) is suitably performed under the same conditions asdescribed above for the condensation between compounds (I) and (II), or(I') and (III).

The substituted benzaldehydes of formulae (II) and (III) are knowncompounds or can be prepared from readily available starting materialsby conventional methods. The 1,4-diacetyl-2,5-piperazinedione used as astarting material in the preparation of compounds of formula (I) may beprepared by treating 2,5-piperazinedione (glycine anhydride) with anacetylating agent. The acetylation may be performed using anyconventional acetylating agent, for example acetic anhydride underreflux or, alternatively, acetic anhydride at a temperature below refluxin the presence of 4-dimethylaminopyridine.

Compounds of formula (I) may also be prepared by the microwaveirradiation of a mixture comprising 1,4-diacetyl-2,5-piperazinedione, acompound of formula (III) and potassium fluoride on alumina (as base) inthe absence of solvent.

Compounds of formula (I) may alternatively be prepared directly from2,5-piperazinedione (glycine anhydride) by a process which comprisestreating the 2,5-piperazinedione with a mixture comprising a compound offormula (III), sodium acetate and acetic anhydride at an elevatedtemperature, for example under reflux.

Compounds of formula (I') may be prepared by analogous processes,replacing compound (III) in each case by a compound of formula (II).

Compounds of formula A may also be prepared by a process comprising themicrowave irradiation of (i) a mixture comprising a compound of formula(I) as defined above, a compound of formula (II) and potassium fluorideon alumina, or (ii) a mixture comprising a compound of formula (I') acompound of formula (III) and potassium fluoride on alumina, or (iii) amixture comprising 1,4-diacetyl-2,5-piperazinedione, a compound offormula (II), a compound of formula (III) and potassium fluoride onalumina. The irradiation is performed in the absence of a solvent.

Compounds of formula (A) may also be obtained directly by a processwhich comprises condensing together 1,4-diacetyl-2,5-piperazinedione, acompound of formula (II) and a compound of formula (III) in the presenceof a base in an organic solvent. Suitable bases, solvents and reactionconditions are as described above for the condensation reaction between,for example, compounds (I) and (II).

An alternative direct process for the preparation of compounds offormula (A) comprises condensing together 2,5-piperazinedione, acompound of formula (II) and a compound of formula (III) in the presenceof sodium acetate and acetic anhydride at elevated temperature, forexample under reflux.

An alternative process for the preparation of compounds of formula (I)comprises treating a compound of formula (V): ##STR7## wherein R₆ to R₈are as defined above, X is a halogen and R' is a C₁ -C₆ alkyl group,with ammonia followed by acetic anhydride.

Compounds of formula (I') may be prepared by an analogous process whichcomprises treating a compound of formula (V'): ##STR8## wherein R₁ toR₅, X and R¹ are as defined above, with ammonia followed by aceticanhydride.

X in formula (V) or (V') is typically iodine. R¹ is, for example, a C₁-C₄ alkyl group such as a methyl, ethyl, propyl, i-propyl, butyl,sec-butyl or tert-butyl group.

A review of synthetic approaches to unsaturated 3-monosubstituted and3,6-disubstituted-2,5-piperazinediones is provided in Heterocycles,1983, 20, 1407 (C.Shin).

Compounds of formula (A) may be converted into pharmaceuticallyacceptable salts, and salts may be converted into the free compound, byconventional methods. Suitable salts include salts with pharmaceuticallyacceptable, inorganic or organic, bases, or pharmaceutically acceptableinorganic or organic acids. Examples of inorganic bases include ammoniaand carbonate, hydroxides and hydrogen carbonates of group I and groupII metals such as sodium, potassium, magnesium and calcium. Examples oforganic bases include aliphatic and aromatic amines such as methylamine,triethylamine, benzylamine, dibenzylamine or α- or β-phenylethylamine,and heterocyclic bases such as piperidine, 1-methylpiperidine andmorpholine. Examples of inorganic acids include hydrochloric acid,sulphuric acid and orthophosphoric acid. Examples or organic acidsinclude p-toluenesulphonic acid, methanesulphonic acid, mucic acid andbutan-1,4-dioic acid.

Compounds of formula (A) may also be converted into pharmaceuticallyacceptable esters. Suitable esters include branched or unbranched,saturated or unsaturated C₁ -C₆ alkyl esters, for example methyl, ethyland vinyl esters.

Preferred compounds of formula A are depicted by means of theirsubstitution patterns in Table 1 which follows. The compound numberingis adhered to in the rest of the specification. Characterising data forthe compounds are set out in Table 2 in Example 16.

The diketopiperazines of formula (A) and their pharmaceuticallyacceptable salts and esters (referred to hereinafter as the "presentcompounds") have utility as inhibitors of PAI. Elevated levels of PAI-1,by reducing the net endogenous fibrinolytic capacity, can contribute tothe pathogenesis of various thrombotic disorders including myocardialinfarction, deep vein thrombosis and disseminated intravascularcoagulation. The present compounds therefore can act as inhibitors ofthe tPA/PAI-1 interaction. The present compounds can be used in thetreatment of haemostatic disorders. A human or animal, e.g. a mammal,can therefore be treated by a method comprising administration of atherapeutically effective amount of a diketopiperazine of formula (A) ora pharmaceutically or veterinarily acceptable salt thereof.

Tissue plasminogen activator (tPA) is used as a fibrinolytic agent inthe treatment of thrombotic disorders. The efficacy of the tPA in thisrole may be enhanced if it is administered together with a PAIinhibitor. A human or animal, e.g. a mammal, can therefore be treated bya method comprising the combined administration of a therapeuticallyeffective amount of tPA and a therapeutically effective amount of anyone of the present compounds. The present invention also providesproducts containing a diketopiperazine of formula (A) or apharmaceutically acceptable salt or ester thereof and tPA as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of thrombotic disorders, for example where there isinappropriate PAI activity. In such products the present compound isformulated for oral or parenteral (intravenous, intramuscular orsubcutaneous) administration and the tPA is formulated for intravenousadministration.

As one example, during acute myocardial infarction (MI) one of thepresent compounds may be administered to a patient together with tPA toenhance the efficacy of the tPA treatment. As a further example, earlyre-occlusion following treatment of a patient with tPA may be preventedby the post-MI administration of one of the present compounds.

The compounds of formula (A) have been tested in a PAI functional assay.In this assay, a compound is incubated with PAI-1 prior to addition tothe tPA assay system. Inhibition of PAI-1 results in the production ofplasmin from plasminogen. In turn, plasmin cleaves the chromogenicsubstrate S2251 (Kabi Vitrum) producing pNA (p-nitroaniline) which isdetected spectrophotometrically at 405 nm (K. Nilsson et al,Fibrinolysis (1987) 1, 163-168). The results of the assay are reportedin Example 1 which follows.

The present compounds can be administered in a variety of dosage forms,for example orally such as in the form of tablets, capsules, sugar- orfilm-coated tablets, liquid solutions or suspensions or parenterally,for example intramuscularly, intravenously or subcutaneously. Thepresent compounds may therefore be given by injection or infusion.

The dosage depends on a variety of factors including the age, weight andcondition of the patient and the route of administration. Typically,however, the dosage adopted for each route of administration when acompound of the invention is administered alone to adult humans is 0.001lo 10 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight.Such a dosage may be given, for example, from 1 to 5 times daily bybolus infusion, infusion over several hours and/or repeatedadministration. When one of the present compounds is administered incombination with tPA to adult humans, the dosage adopted for each routeof administration is typically from 0.001 to 10 mg, more typically 0.01to 5 mg per kg body weight for a compound of the invention and from 5 to500 mg administered intravenously for the tPA. A suitable dosage regimenfor the tPA is 100 mg given intravenously over 3 hours as follows: 10%of the total dose as an i.v. bolus over 1-2 minutes, 50% of the totaldose as an infusion over 1 hour, 40% of the total dose as an infusionover the subsequent 2 hours.

A diketopiperazine of formula (A) or a pharmaceutically acceptable saltor ester thereof is formulated for use as a pharmaceutical or veterinarycomposition also comprising a pharmaceutically or veterinarilyacceptable carrier or diluent. The compositions are typically preparedfollowing conventional methods and are administered in apharmaceutically or veterinarily suitable form. An agent for use as aninhibitor of PAI comprising any one of the present compounds istherefore provided.

For example, the solid oral forms may contain, together with the activecompound, diluents such as lactose, dextrose, saccharose, cellulose,corn starch or potato starch; lubricants such as silica, talc, stearicacid, magnesium or calcium stearate and/or polyethylene glycols; bindingagents such as starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agentssuch as starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs, sweeteners; wetting agents such aslecithin, polysorbates, lauryl sulphates. Such preparations may bemanufactured in known manners, for example by means of mixing,granulating, tabletting, sugar coating, or film-coating processes.

Liquid dispersions for oral administration may be syrups, emulsions andsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular, a syrup for diabetic patients can contain as carriers onlyproducts, for example sorbitol, which do not metabolise to glucose orwhich only metabolise a very small amount to glucose. The suspensionsand the emulsions may contain as carrier, for example, a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcelluloseor polyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptable carriersuch as sterile water, olive oil, ethyl oleate, glycols such aspropylene glycol, and, if desired, a suitable amount of lidocainehydrochloride. Some of the present compounds are insoluble in water. Acompound may be encapsulated within liposomes.

The following Examples illustrate the invention:

EXAMPLE 1 Testing of the Present Compounds as PAI Inhibitors

Compounds of formula (A) were tested in a PAI chromogenic substrateassay. In the assay (K.Nilsson, Fibrinolysis (1987) 1, 163-168) eachcompound was incubated with PAI-1 prior to addition to the tPA assaysystem. Inhibition of PAI-1 by the compound of formula (Aa) resulted inthe production of plasmin from plasminogen. In turn, the plasmin cleavedthe chromogenic substrate S2251 (Kabi-Vitrum) producing pNA(p-nitroaniline) which was detected spectrophotometrically at 405 nm.

The degrees of inhibition observed in the chromogenic substrate assay atvarious concentrations of compounds of formula (A), or the IC₅₀ values,are presented in Table 1.

                  TABLE 1    ______________________________________    Compound  Concentration in μM    No.       100     50      25    12.5   6.25    ______________________________________    1852      72      71      74    67     4    1920      68      66      57    50     33    1954      16      43      67    57     37    1955      9       2       3     2      0    1956      61      69      69    65     31    1957      10      1       2     1      1    1960      32      64      67    63     56    1962      2       2       1     1      1    1969      52      20      6     0      2    1978      50      41      11    0      3    1981      51      41      26    7      --    1885      54      31      2     0      0    1887      83      46      24    5      0    1889      49      38      15    3      0    1907      80      69      37    23     10    1908      74      69      66    29     12    1909      17      31      53    57     39    1911      38      23      15    20     13    1913      71      54      19    14     15    1924      64      38      18    7      9    1946      7       1       1     1      --    1947      1       1       1     1      0    1949      3       1       1     1      1    1951      43      23      2     1      0    1952      63      37      19    1      0    1953      0       0       1     1      1    1977      54      47      47    20     0    1979      37      0       0     0      0    1980      66      41      51    13     0    1984      17      0       0     0      --    ______________________________________    Compound  Concentration in μM    No.       60      30      15    7.5    3.75    ______________________________________    1914      27      17      15    15     20    1961      48      49      41    11     1    ______________________________________    Compound   Concentration in μM    No.        100 μM                       50 μM  20 μM                                       IC.sub.50    ______________________________________    5058       67      68        75    6.0-3.0    5060.HCl   75      65        52    25.0-12.0    5065.HCl   85      80        12    50.0-20.0    5068.HCl   75      76        81    12.0-6.0    5070.HCl   40      6         6    5080.HCl   62      48        10    50.0-25.0    5186       46                10    5187       58                10    100.0    5201       47                43    2.50    5208       32                10    5209                               1.40    5210                               67.0    5228                               1.10    5229                               3.70    5230       9                 30    0.75    5231       36                42    1.50    5232       10    5233       50                47    2.50    5234       10    5235                               6.0    5236                               2.80    5237       67                72    4.0    5238       36                3    5239       68                65    7.0    5240       46                65    6.50    5241       21                1    5245                               1.80    5246                         34    5248       10    5249       55                10    5250       25                10    14.0    5251       71                      67.0    5254       79                76    35.0    5255       33                80    15.0    5256       65                10    100.0    5259       10                10    5260                               17.0    5343                         20    5344                         40    5345                         39    5346                         15    5347                         39    5348                         15    5360                         59    3.50    5365                               6.50    5365.HCl                           3.30    5372                               11.0    5373                               13.0    5374                               15.0    5375                               4.50    5378                         50    20.0    5380                               15.0    5381                               15.0    5385                               2.0    5398                         54    4.20    5401                         42    ______________________________________

EXAMPLE 2 Pharmaceutical Composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of theinvention can be manufactured as follows:

Composition for 10,000 tablets

compound of the invention (250 g)

lactose (800 g)

corn starch (415 g)

talc powder (30 g)

magnesium stearate (5 g)

The compound of the invention, lactose and half of the corn starch aremixed. The mixture is then forced through a sieve 0.5 mm mesh size. Cornstarch (10 g) is suspended in warm water (90 ml). The resulting paste isused to granulate the powder. The granulate is dried and broken up intosmall fragments on a sieve of 1.4 mm mesh size. The remaining quantityof starch, talc and magnesium stearate is added, carefully mixed andprocessed into tablets.

Reference Example 1 Preparation of(3Z,6Z)-3-benzvyidene-6-(4-methoxybenzylidene)-2,5-piperazinedione (3)##STR9## 1,4-Diacetyl-2,5-piperazinedione (8)

1,4-Diacetylpiperazine-2,5-dione (8) was prepared by the publishedprocedure (S. M. Marcuccio and J. A. Elix, Aust. J. Chem., 1984, 37,1791).

(3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9)

(3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) wasprepared by the published procedure (T. Yokoi, L-M. Yang, T. Yokoi, R-Y.Wu, and K-H. Lee, J. Antibiot., 1988, 41, 494).

(3Z,6Z)-3-Benzylidene-6-(4-methoxybenzylidene)-2,5-piperazinedione (3)

A mixture of (3Z)-1-acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione(9) (1.0 g, 3.6 mmol), benzaldehyde (430 μl, 4.2 mmol) and triethylamine(1.14 ml), 8.2 mmol), in dry DMF (20 ml), was heated at 130° C. for 18h. The reaction mixture was cooled to room temperature and poured intoethyl acetate (100 ml). A yellow solid precipitated which was filteredoff and dried. Yield 360 mg (31%). C₁₉ H₁₆ N₂ O₃

¹ H nmr (400 MHz d₆ -DMSO): δ: 3.80 (3H, s, o-Me); 6.77 (1H, s, CH═C);6.78 (1H, s, CH═C); 6.98 (2H, d, J=8 Hz, 2×C-H on Ar-OMe); 7.30-7.56(7H, m, Ph and 2×C-H on Ar-OMe); 10.15 (2H, br.s, N-H).

¹³ C nmr (100 MHz d₆ -DMSO); δ: 58.68; 117.66; 118.03; 118.77; 128.11;128.92; 129.95; 131.53; 132.11; 132.69; 134.44; 136.59; 161.39; 161.62;162.71. ms (desorption chemical ionisation, ammonia): m/z (% relativeintensity): 321 (100) MH⁺. ir: KBr (diffuse reflectance): max (cm⁻¹):1620, 1700, 3100, 3220. Elemental analysis: Calculated for C₁₉ H₁₆ N₂ O₃: C 71.24, H 5.03, N 8.74. Found: C 70.92, H 5.02, N 8.80. C 70.89, H5.06, N 8.79%

Reference Example 2 Preparation of(3Z,6Z)-3-benzylidene-6-(4-methoxybenzylidene)-1-methyl-2,5-piperazinedione(1) ##STR10##

Compound 16 is treated with ammonia and subsequently with aceticanhydride to yield 1-acetyl-3-benzylidenepiperazine-2,5-dione (18).

Compound 18 is then condensed, in the presence of caesium carbonate ortriethylamine in DMF, with 4-methoxybenzaldehyde to yield compound 3.

Reference Example 3 Preparation of1-acetyl-3-benzylidene-2,5-piperazinedione

1,4-Diacetyl-2,5-piperazinedione (25.0 g, 126 mmol), which is compound(8) mentioned in Reference Example 1 was heated at 120-130° C. in DMF(200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0ml, 126 mmol). After 4 h the mixture was cooled to room temperature andpoured into EtOAc (1000 ml), and washed three times with brine. Anysolid formed at this stage was filtered off. The filtrate was dried(MgSO₄) and the solvent removed in vacuo. The residue was recrystallisedfrom EtOAc:Hexane to give 11.78 g (38%) of the title compound as ayellow solid.

¹ H NMR (CDCl₃ 400 MHz) δ=2.69 (3H, s) 4.54 (2H, s) 7.20 (1H, s) 7.40(3H, m), 7.48 (2H, m), 7.93 (1H, br.s); MS(DCI,NH₃): 262 (MNH₄ ⁺, 20%),245 (MH⁺, 53%), 220 (52%), 204 (100%), 203 (100%)

    ______________________________________    Microanalysis                C            H      N    ______________________________________    Calc        63.93        4.95   41.47    Found       64.11        5.02   11.41                64.05        4.90   11.44    ______________________________________

EXAMPLE 3 Preparation of compound 1908

1-Acetyl-3-benzylidene-2,5-piperazinedione (one equivalent), preparedaccording to Reference Example 2, was treated with4-(3-dimethylaminopropoxy)benzaldehyde in the presence of Cs₂ CO₃ (1-1.1equivalents) in DMF at 80-100° C. for 1-8 hours. The title compound wasobtained in 51% yield.

By the same method, but replacing 4-(3-dimethylaminopropoxy)benzaldehydeby the appropriately substituted benzaldehyde, the following compoundswere prepared:

    ______________________________________    Compound  Yield (%)   Compound  Yield (%)    ______________________________________    1889      41          1950      24    1913      37          1951      49    1924      44          1953      9    1946      32          1984      15    1949      33.5    ______________________________________

Characterising data for the compounds are set out in Example 14.

Reference Example 4 Preparation of(3Z,6Z)-3-(4-hydroxybenzylidene)-6-(4-methoxybenzylidiene)-2,5-piperazinedione

(3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (1equivalent), which is compound (9) mentioned in Reference Example 1, wastreated with 4-acetoxybenzaldehyde (1 equivalent) in the presence of Cs₂CO₃ (1 to 1.1 equivalents) in DMF at 80 to 100° C. for 1 to 6 hours. Thecompound(3Z,6Z)-3-(4-acetoxybenzylidene)-6-(4-methoxybenzylodiene)-2,5-piperazinedionewas obtained in 21% yield. That compound was then treated with aqueoussodium hydroxide in THF at room temperature for 8 hours to give(3Z,6Z)-3-(4-hydroxybenzylidene)-6-(4-methoxybenzyladine)-2,5-piperazinedione(compound 1519) in 30% yield.

EXAMPLE 4 Preparation of Compounds 1885, 1887 and 1909

Compound 1519, prepared as described in Reference Example 4, was treatedwith (CH₃)₃ CCH₂ C(O)Cl (1 equivalent) in DMF in the presence of sodiumhydride (2 equivalents) at room temperature for 4 hours. Compound 1885was obtained in 29% yield.

Under the same conditions, but replacing the acid chloride by CH₃ (CH₂)₅COCl (1 equivalent) compound 1887 was obtained in 83% yield.

Under conditions analogous to those used in Reference Example 4, butusing the appropriately substituted benzaldehyde and heating at 80° C.for five hours, Compound 1909 was obtained.

EXAMPLE 5 Preparation of Compound 36 and 1947

1,4-Diacetyl-2,5-piperazinedione, Compound (8) mentioned in ReferenceExample 1, was treated with 4-(3-dimethylaminopropoxy)benzaldehyde (2equivalents) in DMF in the presence of Cs₂ CO₃ (2.1 equivalents) at 90°C. for two hours. Compound 36 was obtained in 50% yield.

Under the same conditions, but using4-(2-dimethylaminoethoxy)benzaldehyde, Compound 1947 was obtained in 30%yield.

EXAMPLE 6 Preparation of Compounds 1907 and 1911

Compound (9), prepared as described in Reference Example 1, was treatedwith 4-n-hexyloxybenzaldehyde in DMF in the presence of Cs₂ CO₃ at 90°C. for two hours. Compound 1907 was obtained in 78% yield.

Under analogous conditions, but replacing the substituted benzaldehydeby 4-(2-dimethylaminoethoxy)benzaldehyde and heating at 80° C. for fourhours, Compound 1911 was obtained in 39% yield.

EXAMPLE 7 Preparation of Compound 1952

1,4-Diacetyl-2,5-piperazinedione, Compound (8) mentioned in ReferenceExample 1, was treated with 2,5-dichlorobenzaldehyde in DMF in thepresence of triethylamine to give1-acetyl-(2,6-dichlorobenzyladiene)-2,5-piperazinedione. This wastreated with 4-(2-dimethylaminoethoxy)benzaldehyde in DMF in thepresence of Cs₂ CO₃ for two hours to give Compound 1952 in 59% yield.

Reference Example 5 Preparation of(3Z)-1-acetyl-3-(4-(3-dimethylamino)propoxybenzylidene)-2,5-piperazinedion

1,4-Diacetyl-2,5-piperazinedione, which is compound 8 described inReference Example 1, was stirred in DMF with4-(3-dimethylamino)propoxybenzaldehyde and triethylamine and heated to120° C.-130° C. for 2-4 hours, to yield the title compound.

EXAMPLE 8 Preparation of 5186

(3Z)-1-acetyl-3-(4-(3-dimethylamino)propoxy)-benzylidene-2,5-piperazinedione,prepared as in Reference Example 5, was treated with2-methylbenzaldehydre in DMF in the presence of Cs₂ CO₃ at 80-90° C. for2-4 hours. Compound 5186 was obtained in 47% yield.

By the same method, but replacing 2-methylbenzaldehyde by theappropriately substituted benzaldehyde, the following compounds wereprepared:

    ______________________________________    Compound  Yield (%)   Compound  Yield (%)    ______________________________________    5060      41          5246      51    5068      48          5247      50    5187      61          5248      31    5201      41          5251      62    5229      45          5252      63    5208      55          5255      20    5209      55          5343      49    5228      44          5344      22    5232      63          5345      68    5233      45          5346      46    5234      70          5347      59    5235      78          5348      46    5236      82          5360      73    5237      73          5365      76    5238      45          5366      89    5239      72          5373      59    5241      67          5374      46    5242      55          5398      28    5375      25          5401      53    5385      71    ______________________________________

EXAMPLE 9 Preparation of 5249

(3Z)-1-acetyl-3-(2-chloro)benzylidene-2,5-piperazinedione was treatedwith 4-(3-dimethylamino)propoxybenzaldehyde, in DMF in the presence ofCs₂ CO₃ at 80° C.-90° C. for 2-4 hours. Compound 5249 was obtained in68% yield.

By the same method, but using a corresponding piperazinedione derivativein which the 2-chloro substituent on the phenyl group of the benzylidenemoiety was replaced by the substituents shown below, the followingcompounds of formula (I) were prepared:

    ______________________________________    Substitution on phenyl group                   Compound of formula (I)                                   Yield (%)    ______________________________________    4-n-butoxy     5250            58    3,5-dichloro   5372            58    3,5-dinitro    5378            72    ______________________________________

By the same method but using(3Z)-1-acetyl-3-benzylidene-2,5-piperazinedione, prepared as inReference Example 3, and 4-(2-diethylamino)ethoxybenzaldehyde thecompound 5065 was prepared in 45% yield.

EXAMPLE 10 Preparation of compounds of formula (I) ##STR11##

(3Z)-1-acetyl-3-(2-bromo)benzylidene was treated with the benzaldehydederivative 10.1 in which Y was O or S, in DMF in the presence of Cs₂ CO₃at 80° C.-90° C. for 2-4 hours, to give compounds 5070 and 5080,respectively, in respective yields of 15% and 28%.

EXAMPLE 11 Preparation of Salts

1. Compound 1981, the salt with hydrochloric acid of Compound 1953, wasprepared by bubbling HCl gas through a solution of Compound 1953 (thecorresponding free base) in THF at room temperature, followed byevaporation to dryness and recrystallization. The salt was obtained in66% yield.

By the same procedure, the following salts were prepared:

    ______________________________________    No of Compounds of Formula (I)                        No of Salt                                 Yield (%)    ______________________________________    1913                1914    1951                1960    1984                1969    1949                1978    1946                1979    1952                1980    5060                5060.HCl 99    5068                5068.HCl 50    5186                5204     32    5187                5203     42    5201                5229     45    5208                5210     27    5209                5231     57    5237                5240     64    5246                5254     18    5247                5256     30    5248                5259     71    5360                5360.HCl 19    5365                5365.HCl 46    5401                5401.HCl 81    5249                5084    5372                5380     86    5378                5381     63    5065                5065.HCl 83    5080                5080.HCl 97    5070                5070.HCl 31    5058                5058.HCl 28    ______________________________________

2. By bubbling HCl gas through a solution of the free base in hot DMF,the following hydrochloride salts of compounds of formula (I) wereprepared:

    ______________________________________    No of Compounds of Formula (I)                        No of Salt                                 Yield (%)    ______________________________________    5228                5230     67    5248                5245     46    5385                5385.HCl 95    5398                5398.HCl 65    ______________________________________

EXAMPLE 12 Preparation of Compound 1977

1-Acetyl-3-(2,4-difluorobenzylidene)-2,5-piperazinedione was prepared bya process analogous to that described in Reference Example 3, butreplacing benzaldehyde by 2,4-difluorobenzaldehyde. That compound wastreated with 4-(3-dimethylaminopropoxy)benzaldehyde in the presence ofCs₂ CO₃ (1 to 1.1 equivalents) in DMF at 80 to 100° C. for 1 to 8 hoursto yield Compound 1977. Compound 1977 was converted to its salt by themethod described in Example 11.

EXAMPLE 13 Preparation of 5260

Compound 5260 was prepared by treating the corresponding phthalimidederivative with hydrazine in H₂ O and THF at room temperature for 5hours.

EXAMPLE 14 Characterization of the Present Compounds

The compounds and salts of the invention were characterised byconventional mass spectroscopic, nmr and microanalytical techniques. Theresulting data are set out in the following Tables:

    __________________________________________________________________________                   Mass spec .sup.1 H nmr    Mol. Formula   m/z. mass Solvent            Microanalysis    No.  (M. Wt)   intensity (mode)                             δ all 400 MHz                                                Calc  Found    __________________________________________________________________________    XR1920         C.sub.27 H.sub.34 O.sub.4 N.sub.3 Cl                   464, 99%. D.sub.4 -MeOH 400 MHz         499.5     C2.sup.+  1.1 (3H, t); 1.6 (2H, m); 2.1 (2H, m); 2.3                             (2H, m); 3.0 (6H, s); 3.5 (2H, m); 4.1 (2H,                             t); 4.3 (2H, t); 4.9 (methanol); 7.0 (2H,                             2×s); 7.1 (2H, d); 7.15 (2H, d); 7.4 (4H,                             t).    XR1914         C.sub.21 H.sub.22 N.sub.3 O.sub.2 Cl                   348 (M±Cl) 100%                             DMSO                             2.72 (6H, s, NMe.sub.2); 4.25 (2H, s, CH.sub.2                             N);                             6.80 (2H, s); 7.32-7.62 (9H, m, Ar); 9.95                             (1H, br.s, NH); 10.25 (2H, br.s, 2×NH).    XR1913         C.sub.21 H.sub.21 N.sub.3 O.sub.2                   347 (M+, 30%),                             DMSO         347       303 (M+-NMe.sub.2,                             2.15 (6H, s, 2×Me); 3.40 (2H, s, CH.sub.2                             Ar);                   80%), 130 (75%); 58                             6.75 (2H, s); 7.35-7.55 (9H, m, aryl CH);                   (100%, possibly                             10.20 (2H, br.s, 2×NH).                   CH.sub.2 NMe.sub.2).                   EI    XR1911         C.sub.23 H.sub.25 N.sub.3 O.sub.4                   408 (MH+, 12%),                             CDCl.sub.3 /TFA         407       350 (MH+-CH.sub.2 NMe.sub.2,                             3.08 (6H, s, NMe.sub.2); 3.64-3.67 (2H, m); 3.88                   10%), 58 (100%).                             (3H, s, OMe); 4.38-4.44 (2H, m); 6.95-7.45                   EI        (10H, m, aryl CH).    XR1909         C.sub.26 H.sub.27 N.sub.3 O.sub.6                   495 (M.sup.+ +NH.sub.4,                             CDCl.sub.3 +TFA         477       13%); 478 (M.sup.+ +1,                             2.00-2.17 (2H, m); 2.45-2.52 (4H, m);                   100%); 446 (M.sup.+-                             3.75 (3H, s, Me); 3.88 (3H, s, Me); 4.50                   OMe, 15%).                             (2H, s); 7.00-7.40 (10H, m).                   EI    XR1908         C.sub.22 H.sub.23 N.sub.3 O.sub.3                   378 (M.sup.+ +1, 100%).                             CDCl.sub.3 +TFA         377       EI        3.10 (6H, s, 2×Me); 3.65 (2H, t,                             CH.sub.2); 4.40                             (2H, t, CH.sub.2); 6.95-7.50 (11H, m).    XR1907         C.sub.25 H.sub.28 O.sub.4 N.sub.2                   421 (98%) CDCl.sub.3 400 MHz                   C2+       0.90 (3H, t); 1.3 (4H, m); 1.5 (2H, m); 1.8                             (2H, m); 3.9 (3H, s); 4.1 (2H, t); 7.0 (4H,                             d×d); 7.2 (4H, s); 7.25 (1H, s); 7.4 (4H,                             d×d); 10.1 (1H, s).    XR1889         C.sub.24 H.sub.24 N.sub.2 O.sub.4                   405 (MH+, 23%); 306                             CDCl.sub.3 /TFA 400                   (100%).   1.16 (9H, s); 2.51 (2H, s); 7.20 (2H, d, J=                   DCl       8 Hz); 7.23 (1H, s); 7.29 (1H, s); 7.40-7.54                   NH        (7H, m).    XR1887         C.sub.26 H.sub.28 N.sub.2 O.sub.5                   449 (MH+, 58%); 448                             CDCl.sub.3 /TFA 400 MHZ         448       (50%); 336 (100%);                             0.95 (3H, t, J=6 HZ); 1.30-1.41 (4H, m);                   146 (43%).                             1.41-1.52 (2H, m); 1.75-1.84 (2H, m); 2.65                             (2H, t, J=6 Hz); 3.95 (3H, s); 7.05 (2H, d,                             J=8 Hz); 7.20-7.31 (4H, m); 7.46 (2H, d,                             J=8 Hz); 7.51 (2H, d, J=8 HZ).    XR1885         C.sub.25 H.sub.26 N.sub.2 O.sub.5                             400 MHZ CDCl.sub.3 TFA                             1.18 (9H, s); 4.54 (2H, s); 3.90 (3H, s); 7.01                             (2H, d, J=8 Hz); 7.15-7.28 (4H, m); 7.40-                             7.49 (4H, m).    XR1852         C.sub.23 H.sub.26 N.sub.3 O.sub.3 Cl                   392 ( M-Cl!+, 100%).                             DMSO 400 MHz                63.16                   ESI       2.15 (2H, m); 3.18 (2H, m); 3.25 (6H,                                                         6.06                             4.10 (2H, t, J=6 Hz); 6.75 (1H, s); 6.77                                                         9.19                             s); 7.00 (2H, d, J=8 Hz); 7.34 (1H, m); 7.42                             (2H, m); 7.52-7.59 (4H, m).    XR1955         C.sub.32 H.sub.42 N.sub.4 O.sub.8.2H.sub.2 O                             DMSO 400 MHz       C  59.43                                                      59.23                                                         59.22                             1.87 (4H, m); 2.21 (12H, s); 2.39 (4H,                                                H);                                                   7.17                                                      7.14                                                         7.07                             2.48 (4H, t, J=6 Hz); 4.06 (4H, t, J=6                                                Nz);                                                   8.66                                                      8.48                                                         8.57                             6.75 (2H, s); 7.00 (4H, d, J=8 Hz); 7.52                             (4H, d, J=8 Hz).    XR1954         C.sub.26 H.sub.29 N.sub.3 O.sub.7                             DMSO 400 MHz       C  63.02                                                      62.75                                                         63.02                             2.29 (6H, s); 2.43 (4H, s); 2.72 (2H, t,                                                H= 5.90                                                      5.81                                                         5.87                             6 Hz); 4.10 (2H, t, J=6 Hz); 6.74 (1H,                                                N);                                                   8.48                                                      8.50                                                         8.49                             6.75 (1H, s); 7.00 (2H, d, J=8 Hz); 7.31 (1H,                             m); 7.40 (2H, m); 7.46-7.58 (4H, m).    XR1953         C.sub.29 H.sub.39 N.sub.5 O.sub.2                   489 18%   CDCl.sub.3 400 MHz         489       403 24%   1.66 (4H, OUI), 2.22 (12H, s), 2.28 (4H, t),                   303 100%  2.48 (2H, t), 3.60 (2H, s), 7.04 (2H, over-                   186 62%   lapping signals), 7.32-7.50 (9H, over-                   141 68%   lapping signals).                   85 97%                   58 85%                   EI+    XR1952         C.sub.22 H.sub.21 N.sub.3 O.sub.3 Cl.sub.2                   MH+ (20%) CDCl.sub.3, CF.sub.3 CO.sub.2 D 400                                                CHz                                                   59.20                                                      58.97                                                         58.96         446/447/449                   445 9     7.43 (m, 4H); 7.33 (m, 1H); 7.25 (s,                                                HH);                                                   4.74                                                      4.73                                                         4.72         9:6:1     447 6     7.13 (s, 1H); 7.00 (d, 2H); 4.42 (t,                                                NH);                                                   9.41                                                      9.23                                                         9.24                   449 1     3.67 (t, 2H); 3.09 (s, 6H).                   CI/NH.sub.3    XR1951         C.sub.22 H.sub.22 N.sub.3 O.sub.3 Cl                   MH+ (100%) 412                             CDCl.sub.3 TFAA         411/413 (3:1)                   (35%) 414 7.51-7.41 (m, 5H), 7.36 (d, 1H), 7.22                   378 (10%) (2×s, 2H), 7.07 (d, 1H), 6.90 (dd, 1H),                   CI/NH.sub.3                             4.42 (t, 2H), 3.65 (t, 2H), 3.07 (s, 6H).    XR1949         C.sub.26 H.sub.32 N.sub.4 O.sub.4                   MH+ (100%) 465                             CDCl.sub.3 400 MHz         464       393 (70%) 8.11 (broad s, 2H), 7.47 (m, 2H), 7.40 (m,                   349 (40%) 3H), 7.05-6.90 (m, 5H), 4.14 (m (2 merged                   194 (20%) triplets), 4H), 2.79 (m (2 merged triplets),                             4H), 2.38 (s, 12H).    XR1948         C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2                   MH+ (100%) 465                             D.sub.2 O 400 MHz         537       (free amine)                             7.6-7.0 (m, 10H), 4.53 (m, 4H), 3.75 (t,                             4H), 3.15 (s, 12H).    XR1947         C.sub.26 H.sub.32 N.sub.4 O.sub.4                   MH+ (100%) 465                             CDCl.sub.3 400 MHz         464                 8.18 (broad s, 2H), 7.35 (m, 2H), 7.0-6.9                             (m, 8H), 4.11 (t, 4H), 2.78 (t, 4H), 2.38                             (s, 12H).    XR1946         C.sub.22 H.sub.23 N.sub.3 O.sub.3                   MH+ (100%) 378                             CDCl.sub.3 400 MHz         377                 8.96 (broad, s, 1H), 8.10 (broad s, 1H),                             7.47-7.32 (m, 7H), 7.06-7.01 (m, 4H), 4.24                             (t, 2H), 2.85 (t, 2H), 2.35 (s, 6H).    XR1924         C.sub.22 H.sub.23 N.sub.3 O.sub.3                   MH+ (100%) 378                             CDCl.sub.3 400 MHz         377       CI/NH.sub.3                             8.12 (br, 2×s, 2H), 7.50-7.35 (m, 7H),                             7.05                             (s, 1H), 7.0-6.95 (m, 3H), 4.11 (t, 2H), 2.78                             (t, 2H), 2.85 (s, 6H).    XR1962         C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2                   233 (100%),                             CDCl.sub.3 +TFA                   465 (10%),                             3.05 (12H, s), 3.55 (4H, m), 4.45 (4H, m),                   929 (50%).                             7.00 4H, d), 7.20 (2H, s), 7.42 (4H, d).    XR1961         C.sub.22 H.sub.24 N.sub.3 O.sub.3 Cl                   MH+ (100%) free                             d.sub.6 -DMSO 400 MHz         413.5     amine 378 10.23 (br, 2H), 7.55-7.30 (m, 6H), 7.17 (m,                   CI/NH.sub.3                             2H), 6.96 (m, 1H), 6.80 (s, 1H), 6.79 (s,                             1H), 4.35 (t, 2H), 3.33 (broad t, 2H), 2.71                             (s, 6H).    XR1960         C.sub.22 H.sub.23 N.sub.3 O.sub.3 Cl.sub.2                   MH+ (100%) 412                             d.sub.6 -DMSO         448       (30%) 414 bath free                             10.30 (s, 1H); 10.23 (s, 1H); 10.10 (broad, s,                   amine     1H); 7.62 (d, 1H); 7.55 (d, 2H); 7.42 (m,                             2H); 7.35 (m, 1H); 7.22 (d, 1H); 7.05 (dd,                             1H); 6.81 (s, 1H); 6.80 (s, 1H); 4.41 (t,                             2H); 3.52 (t, 2H); 2.84 (s, 6H).    XR1957         C.sub.30 H.sub.44 N.sub.4 O.sub.10 S.sub.2                             D.sub.2 O 400 MHz     52.62                                                      52.69                                                         52.70                             2.26 (4H, m); 2.89 (6H, s); 2.99 (12H,                                                   6.48                                                      6.46                                                         6.47                             3.38 (4H, m); 4.24 (4H, m); 6.92 (2H,                                                   8.18                                                      8.13                                                         8.13                             7.18 (4H, d, J=8 Hz); 7.57 (4H, d, J=8 Hz).    XR1956         C.sub.23 H.sub.27 N.sub.3 O.sub.6 S                             DMSO 400 MHz                             2.33 (3H, s); 2.90 (6H, s); 3.55 (2H, J=                             6 Hz); 4.34 (2H, t, J=6 Hz); 6.78 (2H, s);                             7.08 (2H, d, J=8 Hz); 7.35 (1H, m); 7.42                             (2H, m); 7.53-7.62 (4H, m).    XR1984         C.sub.26 H.sub.32 N.sub.4 O.sub.4                   MH+ (100%) 465                             CDCl.sub.3 400 MHz         464       (20%) 393 9.07 (s, br, 1H), 8.08 (s, br, 1H), 7.48-7.35                   CI/NH.sub.3                             (m, 5H), 7.25 (d, 1H), 6.98 (s, 1H), 6.96 (s,                             1H), 6.60 (m, 2H).    XR1981         C.sub.29 H.sub.39 N.sub.5 O.sub.2.3HCl                   526 7% (MHCl)                             DMSO d.sub.6 400 MHz         489+106.5 490 4% (MH+)                             2.28 (4H, V. BROAD SIGNAL), 2.78                   266 100%  (12H, s), 3.15 (8H, V. BROAD                             SIGNAL(s)), 4.40 (2H, BROAD PEAK),                             6.82 (2H, OVERLAPPING SIGNALS), 7.36                             (2H, BROAD SIGNAL), 7.44 (2H, t),                             7.56 (2H, d), 7.64 (2H, BROAD SIGNAL),                             7.75 (1H, BROAD SIGNAL).    XR1980         C.sub.22 H.sub.22 N.sub.3 O.sub.3 Cl.sub.3                   MH+ (100%) 446,                             d.sub.6 -DMSO 400 MHz                                                C  54.73                                                      54.43                                                         54.20         482.5     (60%) 448, (10%) 450,                             10.47 (s, 1H); 10.25 (s, 1H); 10.10 (br,                                                H, 4.59                                                      4.67                                                         4.63                   all free amine; 412                             1H); 7.54 (d, 2H); 7.49 (d, 2H); 7.38                                                Nd,                                                   8.70                                                      8.56                                                         8.51                   (30%).    1H); 7.06 (d, 2H); 6.79 (s, 1H); 6.58 (s,                                                Cl);                                                   22.05                                                      21.40                             4.38 (t, 2H); 3.48 (t, 2H); 2.83 (s, 6H).    XR1979         C.sub.22 H.sub.24 N.sub.3 O.sub.3 Cl                             d.sub.6 -DMSO         413.5               10.18 (s, 1H); 10.02 (s, 1H); 9.83 (br, s,                             1H); 7.55-7.32 (m, 7H); 7.12 (d, 1H);                             7.06 (m, 1H); 6.86 (s, 1H); 6.78 (s, 1H);                             4.39 (t, 2H); 3.50 (br, 2H); 2.81 (s, 6H).    XR1978         C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2                   MH+ (45%) 465 free                             D.sub.2 O 400 MHz         537       amine     7.56 (m, 2H); 7.32 (m, 1H); 7.25-7.20 (m,                   393 (30%),                             4H); 7.05 (s, 2H), 4.52 (t, 4H); 3.72 (t, 4H);                   349 (20%),                             3.06 (s, 12H).                   219 (100%).    XR1977         C.sub.22 H.sub.21 N.sub.3 O.sub.3 F.sub.2                   MH+ 414 (100%)                             CDCl.sub.3 +TFA         413       DCI, NH.sub.3                             3.08 (6H, s); 3.12 (2H, m); 4.40 (sH, m);                             6.97 (4H, m); 7.15 (1H, s); 7.25 (1H, s);                             7.45 (3H, m).    XR1969         C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2                   MH+ (100%) 465 free                             D.sub.2 O 400 MH.sub.2         537       amine     7.65-7.52 (m, 6H); 7.07 (m, 2H); 6.92 (d,                   393 (15%);                             1H); 6.82 (s, 1H); 4.50 (m, 4H); 3.74 (br,                   270 (30%).                             2H); 3.68 (br, 2H); 3.07 (s, 12H).                   CI/NH.sub.3    XR1634         C.sub.20 H.sub.16 N.sub.2 O.sub.4                   366 (M.sup.+ NH.sub.4, 20%),                             CDCl.sub.3 -TFA 400 MHz         348       349 (M.sup.+ OH, 72%),                             3.94 (3H, s); 7.17 (1H, s); 7.23 (1H, s);                   317 (100%).                             7.31-7.55 (8H, m); 8.03 (1H, d).                   CI    __________________________________________________________________________                   Mass spec. data                   mass    .sup.1 H nmr data    No.  Mol. Formula                   (intensity)                        mode                           solvent (field)                                        δ    __________________________________________________________________________    5210 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl                   437 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.15-2.20 (2H, m), 2.80 (6H, m),                                        3.19-3.26                                        (2H, m), 4.11 (2H, t), 6.78 (1H, s),                                        6.98 (1H,                                        s), 7.01 (2H, d), 7.55 (2H, d),                                        7.58-7.69 (2H,                                        m), 7.76-7.81 (1H, m), 8.15 (1H, d),                                        10.25                                        (1H, brs), 10.39 (1H, brs), 10.44                                        (1H, brs).    5060 C.sub.23 H.sub.24 BrN.sub.3 O.sub.3.HCl                   472 (100),                        EI d.sub.6 -DMSO/400 MHz                                        2.16 (2H, m), 2.76 (6H, d), 3.20 (2H,                                        m), 4.10                   470 (100).           (2H, t), 6.73 (1H, s), 6.77 (1H, s),                                        7.01 (2H,                                        d), 7.26 (1H, m), 7.43 (1H, m), 7.53                                        (2H, d),                                        7.59 (1H, m), 7.70 (1H, d), 10.30                                        (1H, brs),                                        10.38 (1H, brs), 10.65 (1H, brs).    5065 C.sub.24 H.sub.27 N.sub.3 O.sub.3                   406 (10)                        CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        1.42 (6H, t), 3.34-3.50 (4H, m), 3.65                                        (2H, t),                                        4.37 (2H, t), 6.95 (2H, d), 7.24 (1H,                                        s), 7.26                                        (1H, s), 7.40-7.52 (7H, m).    5068 C.sub.25 H.sub.30 N.sub.4 O.sub.3.HCl                           CDCl.sub.3 /400 MHz                                        2.35 (2H, m), 2.98 (6H, s), 3.27 (6H,                                        s), 3.40                                        (2H, m), 4.14 (2H, t), 6.96 (1H, s),                                        6.99 (1H,                                        s), 7.18 (2H, d), 7.40 (2H, d), 7.59                                        (2H, d),                                        7.75 (2H, d).    5070 C.sub.23 H.sub.24 BrN.sub.3 O.sub.3.HCl                   472 (25),                        CI d.sub.6 -DMSO/400 MHz                                        2.79 (6H, s), 3.35 (2H, t), 3.80 (2H,                                        t), 4.57                   470 (25).            (2H, s), 6.79 (1H, s), 6.81 (1H, s),                                        7.28 (1H,                                        m), 7.40-7.45 (3H, m), 7.55-7.60 (3H,                                        m),                                        7.70 (1H, m), 9.82 (1H, s), 10.31                                        (1H, s),                                        10.43 (1H, s).    5058 C.sub.23 H.sub.25 N.sub.3 O.sub.2 S                   408 (10)                        CI CDCl.sub.3 /400 MHz                                        2.32 (6H, s), 2.50 (4H, brs), 3.75                                        (2H, s), 7.00                                        (1H, s), 7.02 (1H, s), 7.35-7.50 (9H,                                        m),                                        8.10 (2H, brs).    5080 C.sub.23 H.sub.24 BrN.sub.3 O.sub.2 S.Hcl                           d.sub.6 -DMSO/400 MHz                                        2.74 (6H, s), 2.80 (2H, m), 3.26 (2H,                                        m), 3.87                                        (2H, s), 6.76 (1H, s), 6.79 (1H, s),                                        7.28 (1H,                                        m), 7.44 (2H, d), 7.49 (1H, m), 7.55                                        (2H, d),                                        7.60 (1H, d), 7.74 (1H, d), 10.32                                        (1H, brs),                                        10.44 (1H, brs), 10.49 (1H, brs).    5084 C.sub.23 H.sub.24 N.sub.3 O.sub.2.HCl                           d.sub.6 -DMSO/400 MHz                                        2.16 (2H, m), 2.80 (6H, d), 3.22 (2H,                                        m), 4.12                                        (2H, t), 6.79 (1H, s), 6.81 (1H, s),                                        7.02 (2H,                                        d), 7.40 (2H, m), 7.55 (3H, m), 7.62                                        (1H, m).    5186 C.sub.24 H.sub.27 N.sub.3 O.sub.3                   406 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        1.8-1.9 (2H, m), 2.17 (6H, s), 2.29                                        (3H, s),                                        2.38 (2H, t), 4.05 (2H, t), 6.72 (1H,                                        s), 6.79                                        (1H, s), 6.99 (2H, d), 7.22-7.31 (3H,                                        m), 7.40-                                        7.45 (1H, m), 7.52 (2H, d), 9.90 (1H,                                        brs),                                        10.28 (1H, brs).    5187 C.sub.24 H.sub.27 N.sub.3 O.sub.3                   406 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        1.81-1.90 (2H, m), 2.12 (6H, s),                                        2.34-2.40                                        (5H, m), 4.08 (2H, t), 6.75                                        (2×1H, s), 6.99                                        (2H, d), 7.12-7.18 (1H, m),                                        7.30-7.35                                        (2H, m), 7.39 (1H, brs), 7.51 (2H,                                        d), 9.9 (1H,                                        brs), 10.18 (H, brs).    5201 C.sub.24 H.sub.25 N.sub.3 O.sub.5                   436 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        1.82-1.89 (2H, m), 2.15 (6H, s), 2.35                                        (2H, t),                                        4.1 (2H, t), 6.09 (2H, s), 6.7 (2H,                                        d), 6.95-                                        7.0 (3H, m), 7.01-7.08 (1H, m), 7.18                                        (1H, s),                                        7.5 (2H, d), 10.12 (2H, brs).    5203 C.sub.24 H.sub.27 N.sub.3 O.sub.3.HCl                   406 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        2.12-2.21 (2H, m), 2.35 (3H, s), 2.77                                        (6H, s),                                        3.19-3.23 (2H, m), 4.11 (2H, t), 6.71                                        (1H, s),                                        6.73 (1H, s), 7.01 (2H, d), 7.11-7.15                                        (1H, m),                                        7.29-7.32 (2H, m), 7.39 (1H, s), 7.52                                        (2H, d),                                        10.15 (2H, d), 10.60 (1H, brs).    5204 C.sub.24 H.sub.27 N.sub.3 O.sub.3.HCl                   406 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        2.12-2.21 (2H, m), 2.28 (3H, s), 2.78                                        (6H, s),                                        3.19-3.23 (2H, m), 4.11 (2H, t), 6.76                                        (1H, s),                                        6.81 (1H, s), 7.0 (2H, d), 7.23-7.29                                        (3H, m),                                        7.40-7.45 (1H, m), 7.54 (2H, d), 9.4                                        (1H, brs),                                        10.19 (1H, brs), 10.50 (1H, brs).    5208 C.sub.23 H.sub.24 N.sub.4 O.sub.5                   437 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.81-1.90 (2H, m), 2.18 (6H, s), 2.38                                        (2H, t),                                        4.05 (2H, t), 6.75 (1H, s), 6.98 (1H,                                        s), 7.00                                        (2H, d), 7.50 (2H, d), 7.61 (1H, t),                                        7.69 (1H,                                        d), 7.79 (1H, t), 8.15 (1H, d), 10.35                                        (2H, brs).    5210 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl                   437 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.15-2.20 (2H, m), 2.80 (6H, s),                                        3.19-3.26                                        (2H, m), 4.11 (2H, t), 6.78 (1H, s),                                        6.98 (1H,                                        s), 7.01 (2H, d), 7.55 (2H, d),                                        7.58-7.69                                        (2H, m), 7.76-7.81 (1H, m), 8.15 (1H,                                        d),                                        10.25 (1H, brs), 10.39 (1H, brs),                                        10.44 (1H,                                        brs).    5229 C.sub.24 H.sub.25 N.sub.3 O.sub.5.HCl                   436 (40)                        CI d.sub.6 -DMSO/400 MHz                                        2.12-2.19 (2H, m), 2.75 (6H, s),                                        3.15-3.20                                        (2H, m), 4.10 (2H, t), 6.08 (2H, s),                                        6.70 (1H,                                        s), 6.72 (1H, s), 6.95-7.09 (4H, m),                                        7.16 (1H,                                        s), 7.51 (2H, d), 10.11 (1H, brs),                                        10.18 (1H,                                        brs).    5230 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl                   473 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.10-2.19 (2H, m), 2.78 (6H, s),                                        3.10-3.22                                        (2H, m), 4.11 (2H, t), 6.78 (1H, s),                                        6.80 (1H,                                        s), 7.0 (2H, d), 7.55 (2H, d), 7.79                                        (2H, d),                                        8.22 (2H, d), 10.28 (1H, brs).    5231 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl                   437 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.15-2.20 (2H, m), 2.80 (6H, s),                                        3.19-3.26                                        (2H, m), 4.11 (2H, t), 6.79 (1H, s),                                        6.83 (1H,                                        s), 7.00 (2H, d), 7.55 (2H, d), 7.69                                        (1H, t),                                        7.90 (1H, d), 8.11-8.18 (1H, m),                                        10.28 (1H,                                        brs), 10.65 (1H, brs), 10.69 (1H,                                        brs).    5232 C.sub.24 H.sub.24 N.sub.4 O.sub.3                   417 (100)                        CI CDCl+CF.sub.3 CO.sub.2 D/400 MHz                                        2.29-2.48 (2H, m), 3.05 (6H, s),                                        3.43-3.48                                        (2H, m), 4.15-4.20 (2H, m), 6.96 (2H,                                        d), 7.24                                        (1H, s), 7.25 (1H, s), 7.44 (2H, d),                                        7.60-7.78                                        (4H, m).    5233 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3                   428 (33),                        CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.28 (2H, m), 3.00 (6H, s), 3.40 (2H,                                        m), 4.14                   426 (100).           (2H, t), 7.00 (2H, d), 7.18 (1H, s),                                        7.22 (1H,                                        s), 7.38 (2H, d), 7.42 (2H, d), 7.50                                        (2H, d).    5234 C.sub.24 H.sub.27 N.sub.3 O.sub.4                   422 (52)                        CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.30 (2H, m), 3.02 (6H, s), 3.40 (2H,                                        m), 3.89                                        (3H, s), 4.15 (2H, t), 7.00 (2H, d),                                        7.04 (2H,                                        d), 7.20 (1H, s), 7.22 (1H, s), 7.40                                        (2H, d),                                        7.42 (2H, d).    5235 C.sub.24 H.sub.27 N.sub.3 O.sub.3                   406 (28)                        CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.26 (2H, m), 2.40 (3H, s), 3.04 (6H,                                        s), 3.39                                        (2H, m), 4.15 (2H, t), 6.97 (2H, d),                                        7.15 (1H,                                        s), 7.18 (1H, s), 7.28 (2H, d), 7.35                                        (2H, d),                                        7.40 (2H, d).    5236 C.sub.23 H.sub.23 Cl.sub.2 N.sub.3 O.sub.3                   464 (4),                        CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.30 (2H, m), 3.03 (6H, s), 3.42 (2H,                                        m), 4.15                   462 (24),            (2H, t), 3.98 (2H, d), 6.96 (2H, d),                                        7.10 (1H,                   460 (36),            s), 7.23 (1H, s), 7.27 (1H, m), 7.41                                        (2H, d),                   216 (31).            7.52 (1H, m), 7.56 (1H, d).    5237 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3                   428 (13),                        CI d.sub.6 -DMSO/400 MHz                                        1.85 (2H, m), 2.14 (6H, s), 2.37 (2H,                                        t), 4.04                   426 (39).            (2H, t), 6.73 (1H, s), 6.77 (1H, s),                                        6.97 (2H,                                        d), 7.34 (1H, m), 7.40 (1H, m), 7.42                                        (1H, m),                                        7.50 (2H, d), 7.60 (1H, s), 10.30                                        (2H, brs).    5238 C.sub.27 H.sub.33 N.sub.3 O.sub.3                   448 (54)                        CI d.sub.6 -DMSO/400 MHz                                        1.29 (9H, s), 1.84 (2H, m), 2.15 (6H,                                        s), 2.36                                        (2H, t), 4.02 (2H, t), 6.71 (2H, s),                                        6.98 (2H,                                        d), 7.40-7.51 (6H, m), 10.15 (2H,                                        brs).    5239 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.3                   460 (62)                        CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.30 (2H, m), 3.05 (6H, s), 3.43 (2H,                                        t), 4.15                                        (2H, t), 6.96 (2H, d), 7.23 (1H, s),                                        7.24 (1H,                                        s), 7.41 (2H, d), 7.54 (2H, d), 7.72                                        (2H, d).    5240 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3.HCl                           d.sub.6 -DMSO/400 MHz                                        2.16 (2H, m), 2.75 (6H, s), 3.18 (2H,                                        m), 4.10                                        (2H, t), 6.72 (1H, s), 6.78 (1H, s),                                        7.00 (2H,                                        d), 7.36 (1H, m), 7.41 (1H, m), 7.43                                        (1H, m),                                        7.51 (2H, d), 7.60 (1H, s), 10.21                                        (1H, s), 10.48                                        (1H, s), 10.66 (1H, brs).    5241 C.sub.24 H.sub.27 N.sub.3 O.sub.4                           d.sub.6 -DMSO/400 MHz                                        1.83 (2H, m), 2.12 (6H, s), 2.36 (2H,                                        t), 3.85                                        (3H, s), 4.03 (2H, t), 6.75 (1H, s),                                        6.85 (1H,                                        s), 7.00 (2H, d), 7.02 (1H, m), 7.09                                        (1H, d),                                        7.31 (1H, m), 7.49 (1H, d), 7.51 (2H,                                        d), 9.90                                        (1H, brs), 10.10 (1H, brs).    5242 C.sub.24 H.sub.27 N.sub.3 O.sub.4                           CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        1.95 (2H, m), 2.28 (6H, s), 2.45 (2H,                                        t), 3.83                                        (3H, s), 4.05 (2H, t), 6.89 (1H, s),                                        6.92 (1H,                                        s), 7.00 (5H, m), 7.31-7.42 (3H, m).    5245 C.sub.24 H.sub.24 N.sub.4 O.sub.3 HCI                   417 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        2.10-2.20 (2H, m), 2.80 (6H, d),                                        3.18-3.25                                        (2H, m), 4.11 (2H, t), 6.79                                        (2×1H, s), 7.0 (2H,                                        d), 7.52 (2H, d), 7.70 (2H, d), 7.84                                        (2H, d),                                        10.10 (1H, brs), 10.26 (1H, brs),                                        10.50 (1H,                                        brs).    5246 C.sub.24 H.sub.28 N.sub.4 O.sub.4                   435 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.82-1.88 (2H, m), 2.15 (6H, s), 2.35                                        (2H, t),                                        4.05 (2H, t), 6.75 (1H, s), 6.77 (1H,                                        s), 6.98                                        (2H, d), 7.31 (1H, br), 7.51 (2H, d),                                        7.62 (2H,                                        d), 7.9 (2H, d), 7.96 (1H, br), 10.23                                        (1H, brs).    5247 C.sub.25 H.sub.28 N.sub.4 O.sub.4                   449 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.84-1.90 (2H, m), 2.08 (3H, s), 2.15                                        (6H, s),                                        2.35 (2H, t), 4.05 (2H, t), 6.69 (1H,                                        s), 6.75                                        (1H, s), 6.99 (2H, d), 7.20 (2H, d),                                        7.37 (1H,                                        t), 7.50 (2H, d), 7.61 (2H, d), 7.67                                        (1H, s),                                        9.98 (2H, s), 10.05 (1H, brs).    5248 C.sub.25 H.sub.28 N.sub.4 O.sub.4                   449 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.83-1.90 (2H, m), 2.03 (3H, s), 2.17                                        (6H, s),                                        2.39 (2H, t), 4.04 (2H, t), 6.72 (1H,                                        s), 6.74                                        (1H, s), 6.98 (2H, d), 7.16-7.21 (1H,                                        m), 7.29-                                        7.32 (1H, m), 7.46-7.52 (3H, m),                                        7.60-7.64                                        (1H, m), 9.52 (1H, brs), 10.03 (1H,                                        brs).    5249 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3                   426 (10)                        CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.31 (2H, m), 3.02 (6H, d), 3.42 (2H,                                        m), 4.18                                        (2H, t), 6.95 (2H, d), 7.20 (1H, s),                                        7.28 (1H,                                        s), 7.40 (5H, m), 7.55 (1H, m).    5250 C.sub.27 H.sub.33 N.sub.3 O.sub.4                           CDCl.sub.3 +D.sub.2 O/400 MHz                                        1.00 (3H, t), 1.50 (2H, m), 1.80 (2H,                                        m), 2.00                                        (2H, m), 2.25 (6H, s), 2.50 (2H, t),                                        4.00 (2H,                                        t), 4.05 (2H, t), 6.98-7.04 (6H, m),                                        7.30-7.40                                        (4H, m).    5251 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.3                   460 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.82 (2H, m), 2.15 (6H, s), 2.36 (2H,                                        t), 4.01                                        (2H, t), 6.78 (1H, s), 6.83 (1H, s),                                        6.98 (2H,                                        d), 7.46-7.58 (3H, m), 7.60-7.72 (2H,                                        m), 7.75                                        (1H, d).    5252 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.3                   460 (52)                        CI d.sub.6 -DMSO/400 MHz                                        1.83 (2H, m), 2.19 (6H, s), 2.38 (2H,                                        t), 4.02                                        (2H, t), 6.78 (1H, s), 6.83 (1H, s),                                        6.98 (2H,                                        d), 7.53 (2H, d), 7.62 (2H, m), 7.79                                        (1H, d),                                        7.83 (1H, s), 10.20 (2H, brs).    5254 C.sub.24 H.sub.26 N.sub.4 O.sub.4 HCl                   435 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.10-2.19 (2H, m), 2.79 (6H, s),                                        3.20-3.25                                        (2H, m), 4.08-4.15 (2H, m), 6.77 (1H,                                        s), 6.79                                        (1H, s), 7.0 (2H, d), 7.35 (1H, br),                                        7.55 (2H,                                        d), 7.60 (2H, d), 7.91 (2H, d), 7.99                                        (1H, br),                                        10.19 (1H, brs), 10.32 (1H, brs).    5255           537 (70),                        CI d.sub.6 -DMSO/400 MHz                   407 (50),                   166 (35),                   86 (100).    5256 C.sub.25 H.sub.28 N.sub.4 O.sub.4.HCl                   449 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.05 (3H, s), 2.18-2.28 (2H, m), 2.78                                        (6H,                                        s), 3.15-3.25 (2H, m), 4.11 (2H, t),                                        6.69 (1H,                                        s), 6.75 (1H, s), 7.0 (2H, d),                                        7.18-7.20 (1H,                                        m), 7.34 (1H, t), 7.55 (2H, d),                                        7.59-7.62 (1H,                                        m), 7.69 (1H, s), 9.48 (2H, brs),                                        10.15 (1H,                                        brs).    5259 C.sub.25 H.sub.28 N.sub.4 O.sub.4.HCl                   449 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.01 (3H, s), 2.11-2.18 (2H, m), 2.77                                        (6H,                                        s), 3.19-3.25 (2H, m), 4.11 (2H, t),                                        6.74 (1H,                                        s), 6.76 (1H, s), 7.0 (2H, d),                                        7.18-7.22 (1H,                                        m), 7.28-7.33 (1H, m), 7.48-7.50 (1H,                                        m),                                        7.53 (2H, d), 7.56-7.60 (1H, m), 9.41                                        (1H,                                        brs), 9.89 (1H, brs), 10.09 (1H,                                        brs), 10.18                                        (1H, brs).    5260 C.sub.23 H.sub.26 N.sub.4 O.sub.3                   407 (70)                        CI d.sub.6 -DMSO/400 MHz                                        1.80-1.90 (2H, m), 2.18 (6H, s), 2.39                                        (2H, t),                                        4.03 (2H, t), 5.52 (2H, s), 6.60 (2H,                                        d), 6.65                                        (1H, s), 6.69 (1H, s), 6.98 (2H, d),                                        7.28 (2H,                                        d), 7.48 (2H, d), 9.80 (1H, brs),                                        11.58 (1H,                                        brs).    5343 C.sub.30 H.sub.30 N.sub.4 O.sub.4                   511 (10)                        CI d.sub.6 -DMSO/400 MHz                                        1.85 (2H, m), 2.45 (6H, s), 2.37 (2H,                                        t), 4.05                                        (2H, t), 4.05 (2H, t), 6.78 (1H, s),                                        6.81 (1H,                                        s), 6.99 (2H, d), 7.10 (1H, m), 7.35                                        (2H, m),                                        7.52 (2H, d), 7.70 (2H, d), 7.79 (2H,                                        d), 8.01                                        (2H, d), 10.2-10.3 (3H, br).    5344 C.sub.31 H.sub.32 N.sub.4 O.sub.4                   525 (10)                        CI d.sub.6 -DMSO/400 MHz                                        1.85 (2H, m), 2.15 (6H, s), 2.35 (2H,                                        t), 4.05                                        (2H, t), 4.49 (2H, d), 6.76 (1H, s),                                        6.78 (1H,                                        s), 6.97 (2H, d), 7.22 (1H, m), 7.32                                        (4H, m),                                        7.50 (2H, d), 7.61 (2H, d), 7.91 (2H,                                        d), 9.05                                        (1H, t), 10.2-10.4 (2H, br).    5345 C.sub.32 H.sub.34 N.sub.4 O.sub.4                   539 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.85 (2H, m), 2.15 (6H, s), 2.35 (2H,                                        t), 2.85                                        (2H, t), 3.49 (2H, m), 4.05 (2H, t),                                        6.76 (1H,                                        s), 6.78 (1H, s), 6.99 (2H, d),                                        7.18-7.32 (5H,                                        m,), 7.52 (2H, d), 7.61 (2H, d), 7.85                                        (2H, d),                                        8.55 (1H, brt), 10.20 (2H, br).    5346 C.sub.33 H.sub.36 N.sub.4 O.sub.4                   553 (5)                        CI d.sub.6 -DMSO/400 MHz                                        1.76-1.86 (4H, m), 2.15 (6H, s), 2.34                                        (2H, t),                                        2.62 (2H, t), 3.30 (2H, m), 4.02 (2H,                                        t), 6.73                                        (1H, s), 6.76 (1H, s), 6.96 (2H, d),                                        7.12-7.28                                        (5H, m), 7.49 (2H, d), 7.59 (2H, d),                                        7.86 (2H,                                        d), 8.45 (1H, brt), 10.20 (2H, br).    5347 C.sub.34 H.sub.36 N.sub.4 O.sub.4                   567 (5)                        CI d.sub.6 -DMSO/400 MHz                                        1.52-1.65 (4H, m), 1.85 (2H, m), 2.15                                        (6H, s),                                        2.35 (2H, t), 2.61 (2H, t), 3.30 (2H,                                        m), 4.02                                        (2H, t), 6.73 (1H, s), 6.76 (1H, s),                                        6.96 (2H,                                        d), 7.12-7.27 (5H, m), 7.50 (2H, d),                                        7.61 (2H,                                        d), 7.86 (2H, d), 8.43 (1H, brt),                                        10.20 (2H, br).    5348 C.sub.24 H.sub.24 N.sub.4 O.sub.3                   417 (100)                        CI CDCl.sub.3 /400 MHz                                        2.26-2.35 (2H, m), 3.01 (6H, s),                                        3.39-3.45                                        (2H, m), 4.17-4.20 (2H, t), 6.96 (2H,                                        d), 7.20                                        (1H, s), 7.25 (1H, s), 7.40 (2H, d),                                        7.55 (2H,                                        d), 7.76 (2H, d).    5360 C.sub.23 H.sub.24 BN.sub.3 O.sub.3                   472 (100),                        ESI                           d.sub.6 -DMSO/400 MHz                                        1.80-1.91 (2H, m), 2.12 (6H, s),                                        2.30-2.38                   470 (100).           (2H, m), 4.00-4.08 (2H, m), 6.69 (1H,                                        s), 6.74                                        (1H, s), 6.99 (2H, d), 7.45-7.52 (4H,                                        m), 7.59                                        (2H, d), 10.19 (1H, brs).    5360.HCl         C.sub.23 H.sub.24 BrN.sub.3 O.sub.3.HCl                   471 (100)                        CI d.sub.6 -DMSO/400 MHz                                        2.10-2.20 (2H, m), 2.79 (6H, s),                                        3.19-3.25                                        (2H, m), 4.09-4.25 (2H, m), 6.70 (1H,                                        s), 6.75                                        (1H, s), 7.0 (2H, d), 7.45-7.80 (6H,                                        m), 9.38                                        (1H, brs), 10.15 (1H, brs), 10.30                                        (1H, brs).    5365 C.sub.23 H.sub.24 FN.sub.3 O.sub.3                   410 (100)                        ESI                           CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.28-2.35 (2H, m), 3.05 (6H, s),                                        3.41-3.48                                        (2H, m), 4.18-4.21 (2H, m), 6.96                                        (2×1H, s),                                        7.13-7.27 (4H, m), 7.39-7.48 (4H,                                        m).    5365.HCl         C.sub.23 H.sub.24 FN.sub.3 O.sub.3.HCl                   410 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        2.10-2.20 (2H, m), 2.79 (6H.2), 3.09                                        (2H, m),                                        4.09 (2H, t), 6.75 (2H, s), 7.0 (2H,                                        d), 7.24                                        (2H, t), 7.55 (2H, d), 7.58-7.61 (2H,                                        m), 10.12                                        (1H, br.s), 10.25 (1H, brs).    5366 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3                   416 (100)                        ESI                           CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.29-2.35 (2H, m), 3.03 (6H, s), 3.45                                        (2H, t),                                        4.19 (2H, t), 6.97 (2H, d), 7.21 (1H,                                        s), 7.26                                        (1H, s), 7.37-7.42 (4H, m), 7.48 (2H,                                        d).    5375 C.sub.23 H.sub.24 BrN.sub.3 O.sub.3                   472 (50),                        CI d.sub.6 -DMSO/400 MHz                                        1.83 (2H, m), 2.15 (6H, s), 2.35 (2H,                                        t), 4.02                   470 (50).            (2H, t), 6.70 (1H, s), 6.75 (1H, s),                                        6.97 (2H,                                        d), 7.35 (1H, m), 7.50 (4H, m), 7.69                                        (1H, s),                                        10.30 (2H, br.).    5373 C.sub.23 H.sub.24 FN.sub.3 O.sub.3                   410 (100)                        CI d.sub.6 DMSO/400 MHz                                        1.85 (2H, m), 2.15 (6H, s), 2.35 (2H,                                        t), 4.03                                        (2H, t), 6.75 (1H, s), 6.77 (1H, s),                                        6.99 (2H,                                        d), 7.14 (1H, m), 7.32-7.47 (3H, m),                                        7.50 (2H,                                        d), 10.20 (2H, br).    5374 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.4                   476 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.85 (2H, m), 2.15 (6H.2), 2.35 (2H,                                        t), 4.02                                        (2H, t), 6.75 (2×1H, s), 6.97                                        (2H, d), 7.29 (1H,                                        m), 7.49-7.52 (5H, m), 10.20 (2H,                                        br).    5378 C.sub.23 H.sub.23 N.sub.5 O.sub.7                   482 (100)                        CI d.sub.6 -DMSO/400 MHz                                        1.80-1.90 (2H, m), 2.15 (6H, s), 2.47                                        (2H, t),                                        4.05 (2H, m), 6.75 (1H, s), 6.85 (1H,                                        s), 6.95                                        (2H, d), 7.50 (2H, d), 8.70 (3H, m).    5380 C.sub.23 H.sub.23 Cl.sub.2 N.sub.3 O.sub.3.HCl                           d.sub.6 -DMSO/400 MHz                                        2.15 (2H, m), 2.77 (6H, s), 3.20 (2H,                                        t), 4.10                                        (2H, t), 6.70 (1H, s), 6.78 (1H, s),                                        7.00 (2H, d),                                        7.50-7.55 (5H, m), 10.10 (1H, brs),                                        10.25 (1H,                                        brs), 10.65 (1H, brs).    5381 C.sub.23 H.sub.23 N.sub.5 O.sub.7.HCl                           d.sub.6 -DMSO/400 MHz                                        2.10-2.15 (2H, m), 2.80 (6H, s), 3.20                                        (2H, t),                                        4.10 (2H, t), 6.80 (1H, s), 6.90 (1H,                                        s), 7.00                                        (2H, d), 7.54 (2H, d), 8.65-8.75 (3H,                                        m),                                        10.30 (1H, brs), 10.90 (1H, brs).    5385 C.sub.24 H.sub.27 N.sub.2 O.sub.3 S                   438 (100)                        ESI                           CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.19-2.37 (2H, m), 2.52 (3H, m), 2.56                                        (6H, s),                                        3.43-3.49 (2H, m), 4.18-4.21 (2H, m),                                        6.96                                        (2H, d), 7.25 (2×1H, s),                                        7.32-7.46 (6H, m).    5385.HCl         C.sub.24 H.sub.27 N.sub.2 O.sub.3.HCl                   438 (100)                        ESI                           d.sub.6 -DMSO/400 MHz                                        2.08 (3H, s), 2.10-2.17 (2H, m), 2.81                                        (6H, d),                                        4.11 (2H, d), 6.73 (1H, s), 6.75 (1H,                                        s), 7.00                                        (2H, d), 7.30 (2H, d), 7.50 (2H, d),                                        7.52 (2H,                                        d), 9.76 (1H, brs), 10.10 (1H, brs),                                        10.18 (1H,                                        brs).    5398 C.sub.23 H.sub.21 ClN.sub.4 O.sub.5                           CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400                                        2.29-2.35 (2H, m), 3.05 (6H, s),                                        3.42-3.49                                        (2H, m), 4.17-4.21 (2H, m), 6.98 (2H,                                        d),                                        7.18 (1H, s), 7.29 (1H, s), 7.43 (2H,                                        d),                                        7.55-7.60 (1H, dd), 7.68 (1H, d),                                        7.97                                        (1H, d).    5398.HCl         C.sub.23 H.sub.21 ClN.sub.4 O.sub.5.HCl                           d.sub.6 -DMSO/400 MHz                                        2.09-2.19 (2H, m), 2.72 (6H, s), 3.18                                        (2H, t),                                        4.11 (2H, t), 6.78 (1H, s), 6.80 (1H,                                        s), 7.00                                        (2H, d), 7.55 (2H, d), 7.78 (2H, s),                                        8.18 (1H,                                        s), 10.25 (1H, brs), 10.64 (1H,                                        brs).    5401 C.sub.25 H.sub.27 N.sub.3 O.sub.5                   450 (20)                        CI d.sub.6 -DMSO/400 MHz                                        1.85 (2H, m), 2.15 (6H, s), 2.35 (2H,                                        t), 3.85                                        (3H, s), 4.05 (2H, t), 6.75 (1H, s),                                        6.77 (1H,                                        s), 6.97 (2H, d), 7.50 (2H, d), 7.65                                        (2H, d),                                        7.95 (2H, d), 10.25 (2H, brs).    5401.HCl         C.sub.25 H.sub.27 N.sub.3 O.sub.5.HCl                           d.sub.6 -DMSO/400 Mz                                        2.10-2.20 (2H, m), 2.80 (6H, s),                                        3.20-3.25                                        (2H, m), 3.86 (3H, s), 4.12 (2H, t),                                        6.78 (1H,                                        s), 6.80 (1H, s), 7.00 (2H, d), 7.55                                        (2H, d),                                        7.65 (2H, d), 7.95 (2H, d), 10.10                                        (1H, brs),                                        10.22 (1H, brs), 10.40 (1H,    __________________________________________________________________________                                        brs).

We claim:
 1. A compound which is selected from the group consisting of adiketopiperazine of formula (A): ##STR12## wherein R₁ is H, Cl or--COOMe; R₂, R₃ and R₄ are each independently H or --O(CH₂)_(n) NMe₂wherein n is 1 or 2;R₅ is H or Cl; R₆ is H or F; R₇ is H, OMe or--O(CH₂)_(n) NMe₂ wherein n is 1 or 2; and R₈ is H, F or --O(CH₂)_(n)NMe₂ ; and the pharmaceutically acceptable salts thereof; with theexception of compounds wherein each of R₁ to R₈ is H.
 2. A compoundwhich is selected from the group consisting of a diketopiperazine offormula (A): ##STR13## wherein each of R₁ to R₅ is H; R₆ H, --O(CH₂)_(n)NMe₂, Cl or F;R₇ is H, --O(CH₂)_(n) NMe₂ wherein n is 1 to 2, or OMe;and R₈ is H, --OCOCH₂ --^(t) Bu, --O(CH₂)_(n) NMe₂ wherein n is 1 or 2,--CH₂ NH₂, --CH₂ N (CH₂)₃ NMe₂ !₂ or --OCH₂ CO₂ H; and thepharmaceutically acceptable salts thereof; with the exception ofcompounds wherein each of R₁ to R₈ is H.
 3. A compound according toclaim 2 which is a salt with hydrochloric acid, trifluoroacetic acid,methanesulphonic acid, sulphuric acid, orthophosphoric acid,p-toluenesulphonic acid, or is a sodium or potassium salt.
 4. A compoundselectedfrom:(3Z,6Z)-3,6-Di-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedionedihydrochloride;(3Z,6Z)-3-Benzylidene-6-(4-bis(2-dimethylaminopropyl)aminomethylbenzylidene-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3,6-Di-(4-(2-dimethylaminopropoxy)benzylidene)-2,5-piperazinedionebis methan sulfonate (1:2);(3Z,6Z)-3-Benzylidene-6-(3,4-di-(2-dimethylamnoethoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene-2,5-piperazinedione;(3Z,6Z)-3,6-Di-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedionebis hydrogen succinate (1:2);(3Z,6Z)-3-Benzylidene-6-(4-dimethylaminomethylbenzylidene)-2,5-piperazinedione;Methyl4-(4-((3Z,6Z)-6-(4-Methoxybenzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzylcarbonyl)butanoate;(3Z,6Z)-3-(4-(3,3-dimethylbutanoyloxy)benzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione;(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(2-fluorobenzylidene)-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(2-chloro-4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(2,4-di-(2-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(2,4-di-(2-dimethylaminoethoxy)benzylidene-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(4-bis(3-dimethylaminopropyl)aminomethylbenzylidene)-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3-(2,4-Difluorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3-(4-(2-Dimethylaminoethoxy)benzylidene)-6-(4-methoxybenzylidene-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(2-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione;(3Z,6Z)-3-(4-Aminomethylbenzylidene)-6-benzylidene-2,5-piperazinedionetrifluoroacetate;(3Z,6Z)-3-Benzylidene-6-(4-dimethylaminobenzylidene)-2,5-piperazinedionehydrochloride; and(3Z,6Z)-3-(4-Hexyloxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.5. A pharmaceutical or veterinary composition comprising apharmaceutically or veterinarily acceptable carrier or diluent and, asan active principle, a compound as claimed in claim
 2. 6. A method oftreating a patient suffering from a thrombotic disease, thromboticdisorder or hemostatic disorder, the said disease or disorder beingassociated with elevated levels of PAI-1, which method comprisesadministering to the patient a therapeutically effective amount of acompound selected from the group consisting of a diketopiperazine offormula (A): ##STR14## wherein R₁ is H, a halogen, --COOR₁₁, C₁ -C₆alkyl, NO₂, C₁ -C₆ alkoxy, --NHCOCH₃ or CF₃ ;R₂ is H, --O(CH₂)_(n) N(R₁₁R₁₂), C₁ -C₆ alkyl, NO₂, CN, halogen, C₁ -C₆ alkoxy, CF₃, OCF₃,--NHCOCH₃ or phthalimido; R₃ is H, --O(CH₂)_(n) N(R₁₁ R₁₂), halogen, C₁-C₆ alkoxy, NO₂, C₁ -C₆ alkyl, CF₃, CN, --CON(R₁₁ R₁₂), --NHCOCH₃, --CO₂R₁₁, --CONH(CH₂)_(n) Ph, SR₁₃ or --(CH₂)_(n) N(R₁₁ R₁₂); or R₂ and R₃together form a methylenedioxy group --OCH₂ O--; R₄ is H, halogen, NO₂or --O(CH₂)_(n) N(R₁₁ R₁₂); R₅ is H or a halogen; R₆ is H, a halogen or--O(CH₂)_(n) N(R₁₁ R₁₂); R₇ is H, --O(CH₂)_(n) N(R₁₁ R₁₂) or C₁ -C₆alkoxy; and R₈ is H, a halogen, --O(CH₂)_(n) N(R₁₁ R₁₂), --CH₂Y(CH₂)_(n) N(R₁₁ R₁₂), --OC(O)(CH₂)_(n) R₁₁, C₁ -C₆ alkoxy, --CH₂NHCO(CH₂)_(n) CO₂ R₁₁, --(CH₂)_(n) N(R₁₁ R₁₂), --CH₂ N (CH₂)_(n) N(R₁₁R₁₂)!₂, or --O(CH₂)_(n) CO₂ Hwherein n is 0 or an integer of 1 to 6, Yis O or S, each of R₁₁ and R₁₂ is, independently, hydrogen or a straightor branched C₁ -C₆ alkyl and R₁₃ is straight or branched C₁ -C₆ alkyl;the pharmaceutically acceptable salts thereof and the pharmaceuticallyacceptable esters thereof selected from the group consisting of branchedand unbranched, saturated and unsaturated C₁ -C₆ alkyl esters; with theexception of compounds wherein: (i) each of R₁ to R₈ is H; (ii) R₁ andR₂ are both Cl, Br or F and the rest of R₁ to R₈ are H; R₃ and R₈ areboth the same and are both F, Cl, I, OMe or NMe₂ and the rest of R₁ toR₈ are H; and (iii) R₈ is OMe and the rest of R₁ to R₈ are H.
 7. Amethod of treating a patient suffering from a thrombotic disease orthrombotic disorder, the said disease or disorder being associated withelevated levels of PAI-1, which method comprises administering to thepatient a therapeutically effective amount of a compound as claimed inclaim 4, 1 or
 2. 8. A method of treating a patient suffering from ahemostatic disorder associated with elevated levels PAI-1, which methodcomprises administering to the patient a therapeutically effectiveamount of a compound as claimed in claim 4, 1 or
 2. 9. A methodaccording to claim 7 wherein the patient is suffering from myocardialinfarction, deep vein thrombosis or disseminated intravascularcoagulation.
 10. A method according to claim 6 wherein, in formula(A),R₁ is H, Cl, Me, MeO, NO₂ or --COOMe; R₂ is H, Me, MeO, Cl, Br or--O(CH₂)_(n) NMe₂ ; or R₂ and R₃ together form a methylenedioxy group--OCH₂ O--; R₃ is H, OCH₃, OC₆ H₁₃, O(CH₂)_(n) NMe₂ wherein n is 2 or 3,or CH₂ NMe₂ ; R₄ is H or --O(CH₂)₂ NMe₂ ; R₅ is H or Cl, R₆ is H, Cl orF or --O(CH₂)₂ NMe₂ ; R₇ is H, --O(CH₂)_(n) NMe₂ wherein n is 1 or 2, orOMe; and R₈ is H, F, OMe, --O(CH₂)_(n) NMe, --CH₂ S(CH₂)_(n) NMe₂ or--CH₂ O(CH₂)_(n) NMe₂ wherein n is 1, 2 or 3, --CH₂ NHCO(CH₂)₃ CO₂ Me,--CH₂ NH₂, --(CH₂)_(n) NMe₂ wherein n is 1, 2, 3 or 4; --OCH₂ CO₂ H,--CH₂ N CH₂)₃ NMe₂ ! or --OCO(CH₂)_(n) R₁₁ wherein n is from 1 to 5 andR₁₁ is CH₃ or t-butyl.
 11. A method according to claim 6 wherein, informula (A),each of R₁ to R₅ is H; R₆ is H, --O(CH₂)_(n) NMe₂, Cl or F;R₇ is H, --O(CH₂)_(n) NMe₂ wherein n is 1 or 2, or OMe; and R₈ is H,--OCOCH₂ --^(t) Bu, --O(CH₂)_(n) NMe₂ wherein n is 1 or 2, --CH₂ NH₂,--CH₂ N (CH₂)₃ NMe₂ !₂ or --OCH₂ CO₂ H.
 12. A method according to claim6 wherein, in formula (A), R₁ is H, Cl or --COOMe;R₂, R₃ and R₄ are eachindependently H or --O(CH₂)_(n) NMe₂ wherein n is 1 or 2; R₅ is H or Cl;R₆ is H or F; R₇ is H, OMe or --O(CH₂)_(n) NMe₂ wherein n is 1 or 2; andR₈ is H, F, or --O(CH₂)₂ NMe.
 13. A method according to claim 6 wherein,in formula (A), each of R₆ and R₇ is hydrogen and R₈ is --O(CH₂)_(n)N(R₁₁ R₁₂) or --CH₂ Y(_(CH))_(n) N(R₁₁ R₁₂).
 14. A method according toclaim 6 wherein the patient is suffering from myocardial infarction,deep vein thrombosis or disseminated intravascular coagulation.